Pharma Tips

Rifampicin and Isoniazid in Capsule Formulation

By: Pharma Tips | Views: 4669 | Date: 30-Dec-2012

Tuberculosis is a chronic, progressive infection with a period of latency following initial infection. It occurs most commonly in the lungs. Pulmonary symptoms include productive cough, chest pain, and dyspnea. Diagnosis is most often by sputum culture and smear. Treatment is with multiple antimicrobial drugs.Tuberculosis (TB) is a leading infectious cause of morbidity and mortality in adults worldwide, killing about 1.5 million people every year. HIV/AIDS is an increasingly prominent factor predisposing to

Enhancementof Solubility and Dissolution Rate of Rifampicin and Isoniazid in CapsuleFormulation

Anti tuberculosis formulation

 


1. INTRODUCTION1-10:

1.1 Introduction To Tuberculosis1:

Tuberculosis isa chronic, progressive infection with a period of latency following initialinfection. It occurs most commonly in the lungs. Pulmonary symptoms includeproductive cough, chest pain, and dyspnea. Diagnosis is most often by sputumculture and smear. Treatment is with multiple antimicrobial drugs.

Tuberculosis (TB) is a leading infectiouscause of morbidity and mortality in adults worldwide, killing about 1.5 millionpeople every year. HIV/AIDS is an increasingly prominent factor predisposing toTB infection and mortality in parts of the world where both infections areprevalent.

1.2Types of tuberculosis:

Extra pulmonary Tuberculosis

TBoutside the lung usually results from hematogenous dissemination. Sometimesinfection directly extends from an adjacent organ. Symptoms vary by site butgenerally include fever, malaise, and weight loss.

 

Miliary TB:

Also known asgeneralized hematogenous TB, miliary TB occurs when a tuberculous lesion erodesinto a blood vessel, disseminating millions of tubercle bacilli into thebloodstream and throughout the body. The lungs and bone marrow are most oftenaffected, but any site may be involved. Miliary TB is most common amongchildren < 4 yr, immunocompromised people, and the elderly.

Symptoms include fever, chills, weakness,malaise, and often progressive dyspnea. Intermittent dissemination of tuberclebacilli may lead to a prolonged FUO. Bone marrow involvement may cause anemia,thrombocytopenia, or a leukemoid reaction.

Genitourinary TB:

Infection ofthe kidneys may manifest as pyelonephritis (eg, fever, back pain, pyuria)without the usual urinary pathogens on routine culture (sterile pyuria).Infection commonly spreads to the bladder and, in men, to the prostate, seminalvesicles, or epididymis, causing an enlarging scrotal mass. Infection mayspread to the perinephric space and down the psoas muscle, sometimes causing anabscess on the anterior thigh.

Salpingo-oophoritis can occur after menarche,when the fallopian tubes become vascular. Symptoms include chronic pelvic painand sterility or ectopic pregnancy due to tubal scarring.

TB meningitis:

Meningitisoften occurs in the absence of infection at other extrapulmonary sites. In theUS, it is most common among the elderly and immunocompromised, but in areaswhere TB is common among children, TB meningitis usually occurs between birthand 5 yr. At any age, meningitis is the most serious form of TB and has highmorbidity and mortality. It is the one form of TB believed to be prevented inchildhood by vaccination with BCG.

Symptoms are low-grade fever, unremittingheadache, nausea, and drowsiness, which may progress to stupor and coma.Kernig's and Brudzinski's signs may be positive.

TB peritonitis:

Peritonealinfection represents seeding from abdominal lymph nodes or fromsalpingo-oophoritis. Peritonitis is particularly common among alcoholics withcirrhosis.

Symptoms may be mild, with fatigue, abdominalpain, and tenderness, or severe enough to mimic acute abdomen.

TBpericarditis:

Pericardial infection may develop fromfoci in mediastinal lymph nodes or from pleural TB. In some high-incidenceparts of the world, TB pericarditis is a common cause of heart failure.

Patients may have a pericardial frictionrub, pleuritic and positional chest pain, or fever. Pericardial tamponade mayoccur, causing dyspnea, neck vein distention, paradoxical pulse, muffled heartsounds, and possibly hypotension.

TBlymphadenitis:

Usually, the hilar lymph nodes areinvolved. Other nodes are generally not involved unless the inoculum is largeor poorly contained, allowing organisms to reach the thoracic duct, where theydisseminate into the bloodstream. Most infected nodes heal, but reactivationcommonly occurs. Infection in supraclavicular nodes may inoculate anteriorcervical nodes, eventually resulting in scrofula (TB lymphadenitis in theneck).

Affectednodes are swollen and may be mildly tender or drain.

TB of bonesand joints:

 Weight-bearing joints are most commonlyinvolved, but bones of the wrist, hand, and elbow also may be affected,especially after injure.

Pott'sdisease is spinal infection, which begins in a vertebral body and often spreadsto adjacent vertebrae, with narrowing of the disk space between them.Untreated, the vertebrae may collapse, possibly impinging on the spinal cord.Symptoms include progressive or constant pain in involved bones and chronic orsubacute arthritis (usually monoarticular). In Pott's disease, spinal cordcompression produces neurologic deficits, including paraplegia; paravertebralswelling may result from an abscess.

GastrointestinalTB:

 Because the entire GI mucosa resists TBinvasion, infection requires prolonged exposure and enormous inocula. It isvery unusual in developed countries where bovine TB is rare. Ulcers of themouth and oropharynx may develop from eating M. bovis–contaminated dairyproducts; primary lesions may also occur in the small bowel. Intestinalinvasion generally causes hyperplasia and an inflammatory bowel syndrome withpain, diarrhea, obstruction, and hematochezia. It may also mimic appendicitis.Ulceration and fistulas are possible.

TB of theliver:

 Liver infection is common with advancedpulmonary TB and widely disseminated or miliary TB. However, the livergenerally heals without sequelae when the principal infection is treated. TB inthe liver occasionally spreads to the gallbladder, leading to obstructivejaundice.

Other sites:

Rarely, TB may develop on abraded skin inpatients with cavitary pulmonary TB. TB may infect the wall of a blood vessel andhas even ruptured the aorta. Adrenal involvement, leading to Addison's disease,formerly was common but now is rare. Tubercle bacilli may spread to tendonsheaths (tuberculous tenosynovitis) by direct extension from adjacent lesionsin bone or hematogenously from any infected organ.

1.3 Etiology Of T.B:

TB properly refers only to disease caused byMycobacterium tuberculosis. Similar disease occasionally results from theclosely related mycobacteria, M. bovis, M. africanum, and M. microti.

TB results almost exclusively from inhalationof airborne particles (droplet nuclei) containing M. tuberculosis. Theydisperse primarily through coughing, singing, and other forced respiratorymaneuvers by people who have active pulmonary TB and whose sputum contains asignificant number of organisms (typically enough to render the smearpositive). People with pulmonary cavitary lesions are especially infectious.Droplet nuclei containing tubercle bacilli may remain suspended in room aircurrents for several hours, increasing the chance of spread. However, oncethese droplets land on a surface, it is difficult to resuspend the organisms(eg, by sweeping the floor, shaking out bed linens) as respirable particles.Although such actions can resuspend dust particles containing tubercle bacilli,these particles are far too large to reach the alveolar surfaces necessary toinitiate infection. Fomites (eg, contaminated surfaces, food, and personalrespirators) do not appear to facilitate spread.

Much lesscommonly, spread results from aerosolization of organisms after irrigation ofinfected wounds, in mycobacteriology laboratories, or in autopsy rooms. TB ofthe tonsils, lymph nodes, abdominal organs, bones, and joints was once commonlycaused by ingestion of milk or milk products (eg, cheese) contaminated with M.bovis, but this transmission route has been largely eradicated in developedcountries by slaughtering cows that test positive on a tuberculin skin test andby pasteurization of milk. Tuberculosis due to M. bovis still occurs indeveloping countries and in immigrants from developing countries where bovinetuberculosis is endemic (eg, some Latin American countries).  

Risk factors:HIV infection is the greatest single medical risk factor because cell-mediatedimmunity, which is impaired by HIV, is essential for defense against TB; otherimmunosuppressive illnesses (eg, diabetes) or therapies (eg, tumor necrosisfactor [TNF] inhibitors, corticosteroids) increase risk but less than HIV.

1.5Current Scenario In T.B:

About one third of the world's population isinfected. Of these, perhaps only 15 million have active disease at any giventime. In 2006, an estimated 9.2 million new TB cases occurred worldwide(139/100,000). Of these, Africa and Southeast Asia each accounted for about 3million cases, and the Western Pacific region for about 2 million. Case ratesvary very widely by country, age, race, sex, and socioeconomic status. Indiaand China reported the largest numbers of new cases, but South Africa has thelargest case rate: 940/100,000.

In the US, the case rate has declined 10-foldsince 1953. In 2007 13,299 cases were reported to the CDC for a case rate of4.4/100,000 (ranging from 0.4 in Wyoming to 10.2 in Washington DC). Over halfof these cases occurred in patients born outside the US in high-prevalenceareas. The TB rate among foreign-born people (20.7/100,000) was nearly 10 timesthe rate among US-born people (2.1/100,000). Blacks accounted for 45% of casesamong the US-born. In the southeastern US and inner cities throughout the US,poor US-born blacks, the homeless, people in jails and prisons, and otherdisenfranchised minorities contribute disproportionately to the case rate. Insuch high-risk populations, case rates can approach those in high-burden partsof the world.

1.3 Pathophysiology:

Tuberclebacilli initially cause a primary infection, which only rarely causes acuteillness. Most (about 95%) primary infections are asymptomatic and followed by alatent (dormant) phase. However, a variable percentage of latent infectionssubsequently reactivate with symptoms and signs of disease. Infection isusually not transmissible in the primary stage and is never contagious in thelatent stage.

Primaryinfection: Infection requires inhalation of particles small enough to traversethe upper respiratory defenses and deposit deep in the lung, usually in thesubpleural airspaces of the lower lung. Large droplets tend to lodge in themore proximal airways and typically do not result in infection. Infectionusually begins from a single initial focus.

To initiate infection, tubercle bacilli mustbe ingested by alveolar macrophages. Tubercle bacilli that are not killed bythe macrophages actually replicate inside them, ultimately killing the hostmacrophage (with the help of CD8 lymphocytes); inflammatory cells are attractedto the area, causing a focal pneumonitis that evolves into the characteristictubercles seen histologically. In the early weeks of infection, some infectedmacrophages migrate to regional lymph nodes (eg, hilar, mediastinal), wherethey access the bloodstream. Organisms may then spread hematogenously to anypart of the body, particularly the apical-posterior portion of the lungs,epiphyses of the long bones, kidneys, vertebral bodies, and meninges.

In 95% of cases, after about 3 wk ofuninhibited growth, the immune system suppresses bacillary replication beforesymptoms or signs develop. Foci of infection in the lung or other sites resolveinto epithelioid cell granulomas, which may have caseous and necrotic centers.Tubercle bacilli can survive in this material for years; the balance betweenthe host's resistance and microbial virulence determines whether the infectionultimately resolves without treatment, remains dormant, or becomes active.Infectious foci may leave fibronodular scars in the apices of one or both lungs(Simon foci), calcified scars from the primary infection (Ghon foci), orcalcified hilar lymph nodes. The tuberculin skin test ( Mycobacteria:Skin testing) and the newer interferon-γ release assay becomepositive.

1.6 Remicade:

TB damagestissues through delayed-type hypersensitivity , typically producinggranulomatous necrosis with a caseous histologic appearance. Lung lesions arecharacteristically but not invariably cavitary, especially in immunosuppressedpatients with impaired DTH. Pleural effusion is less common than in progressiveprimary TB but may result from direct extension or hematogenous spread. Ruptureof a large tuberculous lesion into the pleural space may cause empyema with orwithout bronchopleural fistula and sometimes causes pneumothorax. In theprechemotherapy era, TB empyema sometimes complicated medically inducedpneumothorax therapy and was usually rapidly fatal, as was sudden massivehemoptysis due to erosion of a pulmonary artery by an enlarging cavity.

The course varies greatly, depending on thevirulence of the organism and the state of host defenses. The course may berapid among blacks, American Indians, and other populations who have not had asmany centuries of selective pressure to develop innate or natural immunity asdescendents of the European and American TB epidemics have had. The course isoften more indolent in the latter populations.

Acute respiratory distress syndrome (ARDS),which appears to be due to hypersensitivity to TB antigens, develops rarelyafter diffuse hematogenous spread or rupture of a large cavity with spillageinto the lungs.


1.7  Symptomsand Signs:


Symptoms and Signs of TB

 


                                                                            Figure No 2: Symptoms and Signs of TB

 

1.8  Diagnosis:

·        Chest x-ray

·        Tuberculin skin test

·        Acid-fast stain and culture

PulmonaryTB is often suspected on the basis of chest x-rays taken while evaluatingrespiratory symptoms (cough > 3 wk, hemoptysis, chest pain, dyspnea), anunexplained illness, FUO, or a positive tuberculin skin test .

Initial tests are chest x-ray : sputumexamination, and tuberculin skin testing. If the chest x-ray is highlycharacteristic (upper lobe lung cavitation) in patients with TB risk factors,sputum examination is still required, but skin testing is often not done.

Chest x-ray:In adults, a multinodular infiltrate above or behind the clavicle (the mostcharacteristic location, most visible in an apical-lordotic view or with CT)suggests reactivation of TB. Middle and lower lung infiltrates are nonspecificbut should prompt suspicion of primary TB in patients (usually young) whosesymptoms or exposure history suggests recent infection, particularly if thereis pleural effusion. Calcified hilar nodes may be present; they may result fromprimary TB infection but also may result from histoplasmosis in areas wherehistoplasmosis is endemic (eg, the Ohio River Valley).

Sputumexamination:  Sputum is tested forthe presence of acid-fast bacilli (AFB). Tubercle bacilli are nominallygram-positive but take up Gram stain inconsistently; samples are best preparedwith Ziehl-Neelsen or Kinyoun stains for conventional light microscopy orfluorochrome stains for fluorescent microscopy.

Ifpatients cannot produce sputum spontaneously, aerosolized hypertonic saline canbe used to induce it. If induction is unsuccessful, bronchial washings, whichare particularly sensitive, can be obtained by fiberoptic bronchoscopy. Becauseinduction of sputum and bronchoscopy entail some risk of infection for medicalstaff, these procedures should be done as a last resort in selected cases whenMDR-TB is not likely. Appropriate precautions (eg, negative-pressure room, N-95or other fitted respirators) should be used.

Inaddition to acid-fast staining, sputum can be tested using nucleic acidamplification techniques (NAAT) for TB; this test can shorten the time neededto diagnose TB from 1 to 2 wk to 1 to 2 days. However, in low-prevalencesituations, this test is usually done only on smear-positive specimens. It isapproved for smear-negative specimens and isindicated when suspicion is high anda rapid diagnosis is essential for medical or public health reasons.

IfNAAT and AFB smear results are positive, patients are presumed to have TB andtreatment can be started. If the NAAT result is positive and the AFB smearresult is negative, an additional specimen is tested using NAAT; patients canbe presumed to have TB if ≥ 2 specimens are NAAT-positive. If NAAT and AFBsmear results are negative, clinical judgment is used to determine whether tobegin anti-TB treatment while awaiting results of culture.

1..9Prognosis:

Inimmunocompetent patients with drug-susceptible pulmonary TB, even severedisease and large cavities usually heal if appropriate therapy is institutedand completed. Still, TB causes or contributes to death in about 10% of cases,often in patients who are debilitated for other reasons. Disseminated TB and TBmeningitis may be fatal in up to 25% of cases despite optimal treatment.

TB is much more aggressive inimmunocompromised patients and, if not appropriately and aggressively treated,may be fatal in as little as 2 mo from its initial symptom, especially withMDR-TB, in which mortality can approach 90%. With effective antiretroviraltherapy (and appropriate anti-TB treatment), the prognosis forimmunocompromised patients, even with MDR-TB, may approach that ofimmunocompetent patients. However, poorer outcomes should be expected forpatients with XDR-TB because there are so few effective drugs.

1.10 Treatment:

Increasingly,optimal patient case management includes supervision by public health personnelof the ingestion of every dose of drug, a strategy known as directly observedtherapy (DOT). DOT increases the likelihood that the full treatment course willbe completed from 61% to 86% (91% with enhanced DOT, in which incentives andenablers such as transportation vouchers, child care, outreach workers, andmeals are provided). DOT is particularly important

For children and adolescents:

For patientswith HIV infection, psychiatric illness, or substance abuse .After treatmentfailure, relapse, or development of drug resistance.

In some programs, selective self-administeredtreatment (SAT) is an option for patients who are committed to treatment;ideally, fixed-dose combination drug preparations are used to avoid thepossibility of monotherapy, which can lead to drug resistance. Mechanical drugmonitors have been advocated to improve adherence with SAT Public healthdepartments usually visit homes to evaluate potential barriers to treatment(eg, extreme poverty, unstable housing, child care problems, alcoholism, mentalillness) and to check for other active cases and close contacts. Close contactsare people who share the same breathing space for prolonged periods, typicallyhousehold residents, but often include people at work, school, and places ofrecreation. The precise duration and degree of contact that constitutes riskvary because TB patients vary greatly in infectiousness. For patients who arehighly infectious as evidenced by multiple family members with disease orpositive skin tests, even relatively casual contacts (eg, passengers on the busthey ride) should be referred for skin testing and evaluation for latentinfection .patients who do not infect any household contacts are less likely toinfect casual contacts.

1.11 CLASSIFCATION OF ANTI-TUBUARCULAR DRUG8,9,10:

             Table No .01:         

Dosing of First-Line Anti-TB Drugs*

Drug

Adults/Children

Daily

Once/wk

2 Times/wk

3 Times/wk

Isoniazide

Trade name :

INH
NYDRAZID

Adults (maximum)

5 mg/kg (300 mg)

15 mg/kg (900 mg)

15 mg/kg (900 mg)

15 mg/kg (900 mg)

Children (maximum)

10–15 mg/kg (300 mg)

N/A

20–30 mg/kg (900 mg)

N/A

Rifampicin

RIFADIN
RIMACTANE

Adults (maximum)

10 mg/kg (600 mg)

N/A

10 mg/kg (600 mg)

10 mg/kg (600 mg)

Children (maximum)

10–20 mg/kg (600 mg)

N/A

10–20 mg/kg (600 mg)

N/A

Rifabutin Some Trade Names
MYCOBUTIN

Adults (maximum)

5 mg/kg (300 mg)

N/A

5 mg/kg (300 mg)

5 mg/kg (300 mg)

Children

Dosing unknown

N/A

N/A

N/A

Rifapentine Some Trade Names
PRIFTIN


Adults

N/A

10 mg/kg (600 mg)

N/A

N/A

1.12 Treatment regimens:

Treatment ofall patients with new, previously untreated TB should consist of a

1.     2-month initial, intensive phase

2.     4- or 7-month continuation phase

1.12.1 Initial intensive–phase therapy:

Is with 4antibiotics: INH,  RIF,  PZA , and   ETM

(See Table 1:Mycobacteria:Dosing of First-Line Anti-TB Drug). These drugs can be given daily throughoutthis phase or daily for 2 wk, followed by doses 2 or 3 times/wk for 6 wk.Intermittent administration (usually with higher doses) is usually satisfactorybecause of the slow growth of tubercle bacilli and the residual post antibioticeffect on growth (after antibiotic inhibition, bacterial growth is oftendelayed well after antibiotics are below the minimal inhibitory concentration).However, daily therapy is recommended for patients with MDR-TB or HIVco-infection. Regimens involving less than daily dosing must be carried out asDOT because each dose becomes more important.

After2 mo of intensive 4-drug treatment, PZA and usually EMB are stopped, dependingon the drug susceptibility pattern of the original isolate.

1.12.2Continuation-phase treatment:

Depends on results of drug susceptibilitytesting of initial isolates (where available), the presence or absence of acavitary lesion on the initial chest x-ray, and results of cultures taken at 2mo. If positive, 2-mo cultures indicate the need for a longer course oftreatment. If both culture and smear are negative, regardless of the chestx-ray, or if the culture or smear is positive but x-ray showed no cavitation,INH and RIF are continued for 4 more mo (6 mo total). If the x-ray showedcavitation and the culture or smear is positive, INH and RIF are continued for7 more mo either regimen, EMB is stopped if the initial culture shows noresistance to any drug. Continuation-phase drugs can be given daily or, if patientsare not HIV-positive, twice weekly or 3 times weekly..

Forboth initial and continuation phases, the total number of doses (calculated bydoses/week times number of weeks) should be given; thus if any doses aremissed, treatment is extended and not stopped at the end of the time period.

1.12.3Management of drug-resistant TB:

Generally, MDR-TB requires prolonged (eg,18 to 24 mo) treatment with the remaining active first-line drugs (includingPZA, if susceptible) with addition of an injectable, a fluoroquinolone, andother 2nd-line drugs as needed to build a 4- or 5-drug regimen that theinfecting strain is known or likely to be susceptible to (ie, based on testing,a known source-case, prior treatment, or drug susceptibility patterns in thecommunity). Managing the adverse effects of these long, complex regimens ischallenging. MDR-TB should always be treated by a TB specialist experiencedwith these cases. Fully supervised treatment is essential to avoid additionaldrug resistance through nonadherance.

Other treatment: Surgical resection of apersistent TB cavity is occasionally necessary. The main indication forresection is persistent, culture-positive MDR-TB or XDR-TB in patients with adestroyed lung region into which antibiotics cannot penetrate. Otherindications include uncontrollable hemoptysis and bronchial stenosis.

Corticosteroidsare sometimes used to treat TB when inflammation is a major cause of morbidityand are indicated for patients with acute respiratory distress syndrome orclosed-space infections, such as meningitis and pericarditis.

1.12.4 Diagnosis and Treatment11, 12,13, 14:

·        Chest x-ray

·        Tuberculin skin test

·        Acid-fast stain and culture

·        When available, DNA-based testing

 

Drugtreatment is the most important modality and follows standard regimens andprinciple. Six to 9 mo of therapy is probably adequate for most sites exceptthe meninges, which require treatment for 9 to 12 mo. Corticosteroids may helpin pericarditis and meningitis.

Surgeryis required for the following:

·        To drain empyema, cardiac tamponade, and CNSabscess

·        To close bronchopleural fistulas

·        To resect infected bowel

·        To decompress spinal cord encroachment

Surgicaldebridement is sometimes needed in Pott's disease to correct spinal deformitiesor to relieve cord compression if there are neurologic deficits or painpersists; fixation of the vertebral column by bone graft is required in onlythe most advanced cases. Surgery is usually not necessary for TB lymphadenitisexcept for diagnostic purposes

1.13. Introduction to the capsule50

1.13.1 Ideal properties of capsules

1.13.1.1Physicallyparameters

Capsule print or imprint must be legible, andcapsules must be free from chips, cracks, contamination, uneven coloration,etc. capsule must remain whole during manufacture, coating, packaging, andtransport and dispensing. In-process controls include:

 

Table No.02: Physical parameters of capsules

Parameters

Variables

Capsules weight

Limits on capsule weight are generally set as 3 to 5% of a formulation specific target weight Some issues that may cause weight variation are powder flow problems, improper body fill, and powder size distribution.

Capsule slug

hardness

Some issues that may cause variations in capsule slug hardness are inconsistent capsule weight, particle size variations, poor powder compressibility, insufficient binder level

Disintegration      time

The time it takes for the capsule slug to break up into individual granules or particles. Poor disintegration can come from capsules which are pressed too hard, insufficient disintegrate levels, or too much binder.

Moisture level

Empty capsule as usually received range in moisture contain between 12% and 15% .below 10% moisture content, they become brittle and may shrink to the point point of not fitting in to the filling equipment.

 

1.13.1.2Chemically parameters –

The amount of active drug substance specifiedon the label must be present in the   capsule at the time of manufacture and beyond the expiration date.Capsule must have acceptable drug content uniformity. Capsule must haveacceptable drug release characteristics (dissolution).

1.13.1.3 Finished product attributes includes:

Table No. 3: Chemical parameters of capsules

Parameters

Description

Identification

Used to verify that active drug substance in the capsule is correct

Potency

A measure of the amount of active drug substance in the capsule  (i.e. mg/capsule or  % label claim)  Typically in the range of 90 or 95% to 105 or 110%

Related substances

Verifies the quantities of other substances in the product. Limits should be set for other known substances. Unknown substances should fall within ICH guidelines.

Content uniformity

A measure of the consistency of capsule potency, based on the individual analysis of 10 capsules. Typically 85-115% of label claim with a relative standard deviation of <6%.

Dissolution

A measure of the rate and extent of active drug substance going into solution. Dissolution specifications vary depending on the type of capsule made. Typically performed using USP apparatus I (rotating basket) or II (paddle), but may also be done with Apparatus III (Bio-dis) or IV (Flow through cell).

1.13.2Capsule formulation and design:

 

The best newtherapeutic entity in the world is of little value without an appropriatedelivery system. Drug delivery system can range from relatively simpleimmediate release formulation to complex extended or modified release dosageforms.

The general design criteria for capsules are the following,

a) Optimal drug dissolution and hence,availability from the dosage form for absorption consistent with intended use.(i.e. immediate or extended release).

b) Accuracy and uniformity of drug content.

c) Stability, including the stability of the drugsubstance, the overall capsule formulation, disintegration, and the rate andextent of drug dissolution for the capsule for an extended period.

d) Patient Acceptability: As much as possible,the finished product should have an attractive appearance, including color,size, taste etc as applicable in order to maximize patient acceptability andencourage compliance with the prescribed dosing regimen.

e) Manufacturability: The formulation designshould allow for the efficient, cost effective, practical production of therequired batches.

Capsule formulation and design may beprescribed as the process whereby the formulator insures that the correctamount of drug in the right form is delivered at or over the proper time at theproper rate and in the desired location, while having its chemical integrityprotected to that point.

1.13.3 Various steps involve in the formulationand design of capsule -

·       Preformulation:

The Concept of Preformulation

Almost all drugs are marketed as capsule,tablet or both. Prior to the development of these major dosage forms, it isessential that fundamental physical and chemical properties of the drugmolecule and other divided properties of the drug powder are determined. Thisinformation decides many of the subsequent events and approaches in formulationdevelopment. This first learning phase is known as preformulation.

Preformulation involves the application ofbiopharmaceutical principles to the physicochemical parameters of drugsubstance are characterized with the goal of designing optimum drug deliverysystem.

Before beginning the formal preformulationprograms the preformulation scientist must consider the following factors:-

- The amount of drugavailable.

- The physicochemicalproperties of the drug already known.

- Therapeutic category andanticipated dose of compound.

- The nature of information, aformulation should have or would like to have.

Table no.04: Preformulation drugcharacterizations in a structured programmed

Test

Method/ function characterization

Fundamental

1) UV spectroscopy

Simple assay

2) Solubility

Phase solubility/ purity

  a) Aqueous

Intrinsic & pH effect

  b) pKa

solubility control , salt formation  

  c) Salt

Solubility, hygroscopicity & stability

  d)Solvents

Vehicles & Extraction

  e) Dissolution

Biopharmaceutical

3) Melting point

DSC-polymorphism hydrate & solvent

4) Assay development

UV, HPLC, TLC

5) Stability

 

    In solution

Thermal, hydrolysis, pH

    In solid state

Oxidation, proteolysis metal ion

Derived

6) Microscopy

Particle size and morphology

7) Bulk density

Capsule  and tablet formulation

8) Flow properties

Capsule and tablet formulation

9) Compression properties

Acid / excipient choice

10) Excipient compatibility

Preliminary screen by DSC, Confirmation by HPLC

 

1.13.4 Identification of method of manufacture

In this step the formulator has to identify themethod in which the capsule has to be formulated, that is by direct filling ofthe lubricated blend in to capsule. The choice of method is mainly based on thecharacteristics, particle size and particle shape of the drug and theexcipients.


1.14 Manufacturing

In the capsule filling process, it is importantthat all ingredients be dry, powdered, and of uniform grain size as much aspossible. The main guideline in manufactureris to ensure that the amount of active ingredient is equal in each capsule soingredients should be well-mixed. During filling capsules are exerted to greatpressure in order to compact the material. If a sufficiently homogenous mix ofthe components cannot be obtained with simple mixing, the ingredients must becompacted by roller compactor prior to filling to assure an even distributionof the active compound in the final capsule. Two basic techniques are used toprepare powders for filling into a capsule: drymixed lubricated blend and compacted the material by roller compactor andfilled granules of equal shape and size.

1.14.1 Direct filling of lubricated blend: 

This method is used when a group of ingredientscan be blended and placed in a capsule press to make a capsule without any ofthe ingredients having to be changed. This method is used when active materialis sensitive to the temp of the roller compactor.

 Mainly70% of formulation in capsule manufacture is direct filing.

 

1.14.2 Dry granulation by Roller compactor :

This process is usedwhen the product needed to be granulated may be sensitive to moisture. Drygranulation can be conducted on a press using slugging tooling or on a rollercompactor commonly referred to as a chilsonator. Dry granulation equipment offers awide range of pressure and roll types to attain proper densification. However,the process may require repeated compaction steps to attain the proper granuleend point. Process times are often reduced and equipment requirements arestreamlined; therefore the cost is reduced. However, dry granulation oftenproduces a higher percentage of fines or non compacted products, which couldcompromise the quality or create yield problems for the capsule. It requiresdrugs or excipients with cohesive properties.

● Some granular chemicals are suitable for direct compression (freeflowing) e.g.  potassium   chloride.

● Capsule excipients with good flowcharacteristics and compressibility allow for direct compression of a varietyof drugs.

 

1.14.3 Fluidized bed granulation

It is a multiple step process performed in thesame vessel to pre-heat, granulate and dry the powders. It is today a commonlyused method in pharmaceuticals because it allows the individual companies tomore fully control the powder preparation process. It requires only one pieceof machinery that mixes all the powders and granules on a bed of air.

1.14.4 Selection of compatible formulation ingredients:

Knowledge of interaction of drug and excipientsis essential in the initial formulation of a product. It may be necessary lateron during processing scale up, when problem arise, to determine ifincompatibility exist which affect manufacturing or stability.

Drug-excipients interactions are often relatedto the moisture present in one or another of component or to the humidity towhich the formulation is exposed during processing or storage. These studiesare always carried out at accelerated temperature and humidity conditions. Testfor excipient-drug interactions are usually conducted on the blend of the puredrug and excipients in ratios similar to those in the final dosage form.

Nearly all tablet formulation contains one ormore disintegrant to affect capsule break up into smaller particles and tofacilitate dissolution of active ingredients, diluents or filler to exceed thedesired bulk of the capsule, binder to promote bonding and cohesion in thecompact etc.

All the excipients and drug should becompatible with each other.  UtilizeThermal Analysis, to identify possibly compatible or incompatibledrug-excipient combinations. The thermo grams obtained with the drug-excipientsmixtures are compared to thermo grams for the drug alone and excipient alone.Changes in thermo grams of the mixture, such as unexpected shifts, depressions,and addition to or losses from the peaks are considered to be significant.

 

1.14.4 Preparation of trial formulations forin-vitro evaluation:

The following series of steps in the ordergiven may be useful in developing the first trial formulations.

Step 1-Establishthe desired size, dimension and shape.

Step 2-Estimatethe probable weight of an individual capsule as defined in the above

step -II

This may be closely estimated by producing afew individual capsule in a hydraulic press, based on the dose of the drug andmost probable excipients. This step may also yield preliminary data on slug compressibilityand possible compressibility problems.

Step 3-Evaluation of the probable method of manufacturer.

From step 3 above, preformulation data for anew drug or knowledge of the manufacturing for a similar or an identical drug,can provide input into this decision. As noted previously, unless there aremitigating circumstances, direct filling is usually preferred method ofmanufacture.

Steps-Approximatelyestablish the amount of disintegrant, opoaquing agent,plastisizer and otherexcipient ingredients required exclusive of the filler. Add the weights ofthese materials to the weight of the drug per capsule and subtracts the totalfrom the approximate capsule weight determine in step 3. The answer isthe weight of the diluents or filler needed to bring each capsule to thedesired weight.

If the wet granulation is the process to beemployed, this step of sequence is more complicated. If the granulating agentsuch as liquid glucose, which contains a high concentration of solids, isemployed, an estimate may be required of the volume of liquid binder needed to“wet- mass” a particular quantity of powder. The weight of the solids added tothe formulation, upon drying of liquid binder, should be determined anddeducted from the weight of the filler required to achieve the target weight ofthe capsule.

Step 5.In-vitro testing

Various physical and chemical tests areinvolved in this testing.

Step 6.In-vivo testing

Step 7.  Development of stability, bioavailability,validation and clinical data for new drug

 

This final step is undertaken on the selectedformulation after the process has been scaled-up to full production batchsizes.

1.15 Component and additives consideration:

1.15.1 Active ingredients

Drug product viz. capsule consists of an active pharmaceutical ingredient (API)with biologically inert excipients in a compressed, solid form. Anactive ingredient (AI), also known as active pharmaceutical ingredient (API) orbulk active is the substance in a drug that is therapeutically active. Somemedications may contain more than one active ingredient. The traditional wordfor the API is pharmacon (adapted from pharmacos), which originally denoted amagical substance or drug.

1.15.2 Non-active ingrédients(excipients) :

Oral capsules for ingestion usually contain thesame classes of inactive components in addition to the active ingredients,which are one or more agent functioning as diluents, binder, disintegrant,plasticizers, opaquing, preservative and lubricant. Some formulations mayadditionally require a flow promoter, other more optional component includecolorants and sweeteners. All non-drug components are termed as excipients.

Excipientclassification

·        Diluents

·        Binders and adhesives

·        Lubricants

·        Anti-adherents

·        Glidant

·        Disintegrant

·        Colors, flavors andsweeteners

·        Miscellaneouscomponents (e.g.: -buffers and adsorbents)

·        Preservative

·        Plasticizer

·        Opaquing agent

Excipient is any inactive substanceother than the drug substance used in the corresponding drug product. Theinternational pharmaceutical excipients council (IEPC) spells out 13 generalcategories of excipients for solid dosage forms based on function: binders, disintegrant,fillers, lubricants, glidant, compression aids, colors, sweeteners,preservative, suspending/ dispersing agent, film former/coatings, flavors andprinting ink.

1.15.1.1 Factors to consider while choosing excipients for solid dosageforms

Excipients are critical to the design of thedelivery system and play major role in determining its quality and performance.They may be selected to enhance stability (antioxidants, UV absorbers),optimize or modify drug release (disintegrants, hydrophilic polymers, wettingagents, biodegradable polymers), provide essential manufacturing technologyfunctions (binders, glidants, lubricants, antiadherants), enhance patientacceptance (flavor), or aid in product identification (colorants). Moreover,the mechanism of their work, also aids in the suitable choice of excipients.

a) Physiochemical properties of drug

·        Polymorphic/formshydrate

·        Heat/moister sensitive

·        Poorly soluble

·        Poorly absorbable

·        Poor stability in vivo

b) Physiochemical properties of excipients

·        Physically stable

·        Chemically stable

·        Compatible with drug

·        Hygroscopic

·        Rheology flow

Desired release characteristics

·        Immediate release

·        Sustained release

·        Modified release e.g.enteric coated

d) Manufacturing process requirement     

  • Direct compression
  • Wet granulation
  • Fluid bed granulation/coating/spray drying

e) Route of administration

·        Oral

·        Pulmonary

·        Transdermal

·        Buccal /rectal/vaginal

f) Delivered dose of drug

·        High dose, low dose

 

Table no. 5: Lists of different excipientsused in the design of capsules

Excipients

Functions

Examples Table no 2.6 Lists of different excipients used in the design of capsules

Diluents

Used as filler designed to make up the required bulk of the tablet.

Lactose, starch, mannitol, sucrose, sorbitol etc.

Binders and adhesive

These are used to produce cohesive compact, either in dry or wet form.

Acacia, starch, Liquid paraffin , Povidone, Cellulose derivative etc.

Disintegrants

Used to facilitate a breakup of the tablet.

Starch, clays, cellulose, alginate,  povidone etc.

Lubricants

Used to reduce the friction between the granulation and die wall during compression and ejection.

Stearic acid, stearic acid salts, waxes, polyethylene glycol, talc etc

Antiadherants

 

Used to prevent sticking or adhesion of a tablet granules or powder to the faces of punches or die wall.

Talc, polyethylene glycol, hydrogenated castor oil, glycerol beheaded etc.

Glidants or flow promoters

Used to promote flow of the tablet granules or powder material by reducing friction within particles.

Silica derivatives, talc, cornstarch etc.

Colors, Flavors

And sweeteners plasticizer and  preservative.

Used to enhance the organoleptic properties and acceptability of the product.

FD & C, D&C dyes and lakes, banana, bubblegum, strawberry, aspartame,

 

1.16 Biopharmaceutics Classification System (BCS):39,54

In early 90’s Amidon advocated the concept of a scientific framework for classifying drug substances based on their aqueoussolubility and intestinal permeability which gradually came up as the conceptof biopharmaceutics classification system (BCS). The classification isassociated with drug dissolution and absorption model, which identifies the keyparameters controlling drug absorption as a set of dimensionless numbers: theabsorption number, the dissolution number and the dose number.

a) Absorption number is the ratio of the meanresidence time to the absorption time. 

b) Dissolution number is a ratio of meanresidence time to mean dissolution time.

c) Dose number is the mass divided by an uptakevolume of 250 ml and the drug’s solubility.

The mean residence time hereis the average of the residence time in the stomach, small intestine and thecolon. The fraction of dose absorbed then can be predicted based on these threeparameters. For example, absorption number 10 means that the permeation

across the intestinal membrane is 10 timesfaster than the transit through the small intestine indicating 100% drugabsorbed.

BCS is a fundamental guideline for determiningthe conditions under which in-vitro in-vivo correlations are expected. It isalso used as a tool for developing the in-vitro dissolution specification. In the BCS, adrug is classified in one of four classes based solely on its solubility and intestinalpermeability:

Class I drugs such as metoprolol exhibit a high absorption number and ahigh dissolution number. The rate-limiting step to drug absorption is drugdissolution or gastric emptying rate if dissolution is very rapid.

Class II drugs such as phenytoin, have a high absorption number but a lowdissolution number. In-vivo drug dissolution is then a rate-limiting step forabsorption (except at very high dose number). The absorption for Class II drugsis usually slower than Class I and occurs over a longer period of time. IVIVCis usually expected for Class I and Class II drugs.

 ClassIII drugs, permeability is the rate-controlling drug absorption.Furthermore, Class III drugs exhibit a high variability of rate and extent ofdrug absorbed. Since the dissolution is rapid, the variation is due toalteration of GI physiological properties and membrane permeation rather thandosage form factors.

 Class IV drugs are lowsolubility and low permeability drugs. Drugs that fall in this class exhibit alot of problems for effective oral administration. Drug example for class IIIand IV is cimetidine and chlorothiazide, respectively.

Table No. 6:  Overallsummary of BCS classification of drug

Class I

HIGH solubility / High permeability,

Class II

LOW solubility / High permeability,

Class III

HIGH solubility / LOW permeability

Class IV

LOW solubility / LOW permeability.

1.16.1Bioavailability considerations:

The relative amount of an administered dose ofa particular drug that reaches the systemic circulation intact and the rate atwhich this occur is known as the bioavailability .

Many factors affect the drug dissolution ratesfrom the capsules. Hence the possible drug bio-availability considerationsincluding the following,

·     Particle size of drug.

·     Capsules disintegrationmechanism and rate.

·     The method ofgranulation.

·     Type and amount ofbinding agent employed.

·     Type, amount andmethod of incorporation of disintegrant,plastsizer and lubricants.

·     Other formulationprocessing factors.

Also the food eaten by patient, the effect ofthe disease state on drug absorption, the age of the patient, the site (s) ofabsorption of the administered drug, the co administration of other drugs, thephysical and chemical properties of the administered drug, the type of dosageform, the composition and method of manufactured of the dosage form, the sizeof the dose and the frequency of administration are of prime concern, as far asabsorption and bioavailability is in concern.

 

1.18 Steps involved in the different method of manufacture

 Table no. 7: Steps of manufacturing of powder

Step -1

Step -2

Step -3

u Sifting of drug

And excipients.

u Mixing of sifted

Powders.

u Preparation of

Binder solution.

u Wet massing by

Addition of binder     solution to the powder mixture and mixing both.

u Screening of wet-

Mass using

Required # screen.

u Drying of wet

Granules.

u Screening of dry

granules through

Required # screen.

u Screening of lubricants

u Extragranular material.

u Blending of screened granules with extragranular material to produce ‘running powder’.

u Filling into capsule.

u Sifting of drugs and excipients.       

u Mixing of shifted Powders.

u Compression into slugs or

roll compaction.

u Milling and screening of slugs

 and compacted powders.

u Screening of lubricants/

            Extragranular material.

u Mixing with extragranular material

to produce ‘running powder’.

u blend was ready to filled in capsule.

u Sifting of drugs and excipients.

u Mixing of sifted

Powdered ingredients.

u Sifting

of lubricants.

u Blending

with lubricants.

u Filling of  the

Lubricated

Blend into

Capsule.

 

 

1.18.1 Effects of manufacturing process on formulations:

Numerous unit process are involved in makingcapsule, including particle size reduction and sizing, blending, granulatingdrying, compaction and (frequently) coating various factors associated withthese process can seriously affect the content uniformity, bioavailability, orstability. Some of the reasons are listed below,

1.    Particle size reduction

·        Non-uniform particlesize can lead to segregation problems.

·        Development ofelectrostatic forces inhibits complete blending.

·        Changing thecrystalline state can affect solubility

2.   Blending

·        Non-homogeneous distributionof drug substance is the result of poor blending or unbending.

·        Over blending oflubricants lowers the dissolution rates and affects compressibility.

3   Capsule filling

·        Uneven compactionpressures affect dissolution.

·        Loss of mixes qualityin hopper and feed frame lowers dissolution rates.

 

Hence it is essential to critically monitor andestablish the variables during the different stages of manufacturing asdepicted in the table below.

 

Table no.8: Process and productparameter considered during generic solid dosage from manufacture.

Sr.

no.

Pharmaceutical

unit operation

Independent   variables

(Process parameters)

Dependent variable

(Product attributes)

1.     

Dry mix

·         Mix time

·         Impeller chopper speed

·         Lubricant mix time

·         Flow parameter

·         Mix uniformity

·         Compression parameter

·         Dissolution

2.     

Drying

·         Power bed thickness   (Number of tray loaded)

·         Temperature of fluid bed drying, % RH of drying air

·         Duration in oven

·         Moisture content (LOD) as function of time drying rate

·         End point (% LOD)

 

3.     

Fluid bed drying

·         Load

·         Inlet/bed temperature

·         Air flow rate

·         % RH of drying air

·         Moisture content (LOD) as function of time drying rate

·         End point (% LOD)

4.     

Milling  and screening

·            Screen size, blade setting (hammer knives) blade     speed, feed rate

·         Particle size of milled granules

·         Bulk/taped densities of milled    granules

5.     

Blending

·         Blender capacity

·         Mixing time

·         Speed of mixing

·         Blend content uniformity In mixer

·         Particle size and bulk/tapped densities  of final blend

6.     

Encapsulation or capsule filling process .

·         Capsule  press speed

·          Tamping  force (hardness study)

·         Weight and Tamping    force (thickness study)

·         Powder feed rate into die (hopper study)

·         capsule weight, hardness, thickness  study and friability

·         Content uniformity

·         Dissolution/disintegration

·         Assay or potency

 

7.     

Encapsulation

·         Film volume

·         Tamper setting

·         Encapsulation speed

·         Aspiration setting

·         Capsule weight

·         Content uniformity

·         Dissolution

·         Assay or potency

8.     

Roller compaction

·         Roller type

·         Clearance between roller compaction speed and  pressure

·         Granule size of milled compacts

·         Bulk/taped densities of milled compacts.

9.     

Film coating

·         Spray rate

·         Pan speed

·         Airflow rate

·         Pan loading

·         Inlet/exhaust temperature

·         Spray guns assembly and nozzle

·         Coating weight gain

·         Weight variation analysis

·         Assay or potency

·         Dissolution

 

10. 

Fluid

bed coating

·         Inlet temperature

·         Bed temperature

·         Airflow rate, spray rate, rotor speed

·          Assay to determine drug layering

·         Coating weight gain

·         Content uniformity

 

1.18.2 Mechanism of capsule filling:

 Capsule dosage form is often preferred by thepharmaceutical industry for phase I/II clinical study due to several factor.The goal during early-stage development is to develop a simple and stableexploratory formulation that fulfills the clinically discovery goal to evaluatethe safety of compound.

 Stable small-scale capsule formulation can besimple and quicker to develop and required less active pharmaceuticalingredient as compared to tablet.

The type of capsulefilling machines may vary from manual filler to semi automatic type 8 fillingmachine and fully automatic machine like Bosch GKF models.

1.18.3 Manual capsule filling machine:

Step-1: powder spread over the try with several holescontaining the open capsule bodies

Step-2 : the capsule are filled by spreading the powderover bodies with scraper and filled weight increased by tamping the powdermanually in the capsule body with set of tamping pins .

1.18.4 Automatic capsule filling machine:

In Cap tamping typecapsule filling machine with an average encapsulation rate of 3000capsules/hours .low output is use full early stage of development in phase I/IIclinical trial as compared to the high speed capsule filling machine havingoutput 6000/hr.

Step -1: it can encapsulate capsule size 4 to 00 size fourset of tamping pins

Compress powder in to plug within cavities into dosing disc .

Step -2: dosing disc is the stainless steel plate of the definedheight .and each of the 4 tamping stations.

Step -3: powder fills the die and is compressed into plug or bydense coloum by the

Downward motion of the pin. Additional powderis filled in subsequent tamping station followed by additional tamping.

 

The primary objective of this study of thisstudy was to determine the influences of process parameters such as follows:

1.     Tamping pin height.

2.     Height of the powderbed in the dosing disc .

3.     Capsule filling speed.

4.     Flow property of thepowder on fill weight and weight variability.

5.     Shell type – HPMCshell and hard gelatin capsule.

 

1.18.4.1 Corresponding pin setting and correspondingindivual pin setting in Ascending and Descending pin setting order in the in cap

 

 Table no. 9: Individual pin settings

Cumulative pin setting

Ascending                                              

        Descending

pin#1            

pin#2                

pin#3   

pin#1           

pin#2                  

pin#3

12.0

3

3

3

3

3

3

22.5

3

6

6

7.5

6

6

30

3

6

9

12

9

6

33

3

7.5

10.5

12

10

7.5

36

6

7.5

10.5

12

10

7.5

 

1.19 Pharmacokinetic parameter of drug

1.19.1 Pharmacokinetic parameters for Rifampicin:

The critical study of the pharmacokineticparameter is important for development of a drug product.

Table No. 10 Pharmacokinetic parameters for Rifampicin

Name

Rifampicin

Therapeutic Class

 Anti-Tubercular antibiotic

Solubility

Soluble in water .

Pharmacology

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins.[10] Its lipophilic nature makes it a good candidate to treat the meningitis form of tuberculosis, which requires distribution to the central nervous system and penetration through the blood-brain barrier.

Mechanism of Action

Rifampicin inhibits DNA-dependent RNA polymerase in bacterial cells by binding its beta-subunit, thus preventing transcription to RNA and subsequent translation to proteins. Its lipophilic nature which requires distribution to the central nervous system and penetration through the blood-brain barrier.

Rifampicin acts directly on messenger RNA synthesis. It inhibits only prokaryotic DNA-primed RNA polymerase, especially those that are Gram-stain-positive and Mycobacterium tuberculosis. Much of this acid-fast positive bacteria's membrane is mycolic acid complexed with peptidoglycan, which allows easy movement of the drug into the cell.

Absorption

Rifampicin is easily absorbed from the gastrointestinal tract; its ester functional group is quickly hydrolyzed in the bile; and it is catalyzed by a high pH and substrate-specific enzymes called esterases. After about 6 hours, almost all of the drug is deacetylated. Even in this deacetylated form, rifampin is still a potent antibiotic; however, it can no longer be reabsorbed by the intestines and it is subsequently eliminated from the body.

Metabolism and     Elimination

. Only about 7% of the administered drug will be excreted unchanged through the urine, though urinary elimination accounts for only about 30% of the dose of the drug that is excreted. About 60% to 65% is excreted through the feces.

T1/2 Elimination

 1.5 to 5 hrs

Protein Binding

About 60% to 90%

 

1.19.2 Pharmacokinetic Parameters for Isoniazid:

 Thecritical study of the pharmacokinetic parameter is important for development ofa drug product.

Table No. 11: Pharmacokinetic parameters for Isoniazid :

Name

 Isoniazid

Therapeutic Class

 Anti-Tubercular antibiotic .

Solubility

Practicallysoluble in water .

Mechanism of Action

Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase enzyme that in M. tuberculosis is called KatG.[5] KatG couples the isonicotinic acyl with NADH to form isonicotinic acyl-NADH complex. This complex binds tightly to the enoyl-acyl carrier protein reductase known as InhA, thereby blocking the natural enoyl-AcpM substrate and the action of fatty acid synthase. This process inhibits the synthesis of mycolic acid, required for the mycobacterial cell wall. A range of radicals are produced by KatG activation of Isoniazid, including nitric oxide,[6] which has also been shown to be important in the action of another antimycobacterial prodrug PA-824.[7]

Absorption & Excretion

 Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid (CSF), and within caseous granulomas. Isoniazid is metabolized in the liver via acetylation. There are two forms of the enzyme responsible for acetylation, so that some patients metabolize the drug more quickly than others. Hence, the half-life is bimodal with peaks at 1 hour and 3 hours in the US population. The metabolites are excreted in the urine. Doses do not usually have to be adjusted in case of renal failure.

T1/2 Elimination

   0.5-1.6h (fast acetylators), 2-5h (slow acetylators .

Protein Binding

   0.5-1.6h (fast acetylators), 2-5h (slow acetylators .

 

2.1 Rational of the project

1.  Tuberculosis has been declared public emergency byW.H.O.

2.  Rifampicin, Isoniazid, Pyrazinamide and Ethambutol wereearlier prescribed separate formulation in T.B control. W.H.O &International union against tuberculosis and lung disease recommended the useof fixed dose combination formulation of the essential anti T.B drug to ensureadequate treatment.

3.  Moreover, combination therapy with Rifampicin andIsoniazid is more effective in controlling tuberculosis in patients with severecase than the administration of either drug alone. The distinct biologicalactions of Rifampicin and Isoniazid on important component of cell wall synthesis respectively. The combinationtherapy had additional substantial and significant beneficial effects on theseparameters over those seen with monotherapy for either drug. Thus fixed dosecombination of Rifampicin and Isoniazid becomes a better choice in treatment oftubercular diseases.

4.  The strategy is to formulate the Rifampicin andIsoniazid capsule to provide a protection in view of better shelf lifestability.

 Tuberculosis has been treated with combinationtherapy for over fifty years.   Drugs arenot used singly, and regimens that use only single drugs result in the rapiddevelopment of resistance and treatment failure. The rationale for usingmultiple drugs to treat TB are based on simple probability. The frequency ofspontaneous mutations that confer resistance to an individual drug are wellknown: 1 in 107 for EMB, 1 in 108 for STM and INH, and 1in 1010 for RMP.

There is other theoreticalreason for supporting combination therapy. The different    drugs in the regimen have different modes ofaction. INH are bactericidal against replicating bacteria. EMB isbacteriostatic at low doses, but is used in TB treatment at higher,bactericidal doses. RMP is bacteriocidal and has a sterilizing effect. PZA isonly weakly bactericidal, but is very effective against bacteria located inacidic environments, inside macrophages, or in areas of acute inflammation.

2.2 Aim of the project

        The aim of thepresent study was to enhance  thesolubility and dissolution rate of Rifampicin and Isoniazide capsuleformulation.

         These dosage forms are designed to deliver thedrug immediately at the site of action to prevent the  severe infection to the lungs byMycobacterium tuberculosis.   

        Fixed dosecombinations (FDCs) in TB therapy reduce the number of capsule to be consumedand thereby increase patient compliance with recommended treatment regimens.

2.3 Objectiveof the project

1.  To develop a suitable dosage form (capsule) by usingdifferent surfactant and disintegrant for both drugs.

2.  The API Rifampicin known to have low bioavailabilitydue to low solubility properties. The aim is to develop a formulation having animproved solubility and drug release characteristics

3. PLAN OF WORK

 

1.    Literature survey

 

2.    Preformulation studies

·       Organoleptic characteristics

·       Bulk density

·       Tapped density

·       Carr’s Index (Compressibility Index) and Hausner’s Ratio   

·       Determnation of  λ max

·       Drug excipients compatibility study by

·       FTIR spectrometry

·       Particle size analysis by Malvener Analyser

·        HPLC

3.    Evaluation of  Capsule

·         Weight variation

·         Water absorption ratio

·         Wetting time

·       Uniformity of content

·       In-vitro drug release study

 4.     Stability study

Asper I.C.H guideline

 

4. LITTERATUREREVIEW   

4.1 US Patent 5439891- “Process for prepartion of pharmaceutical composition with enhancedactivity for treatment of T.B and Leprosy”

4.2 PanchghulaR, Agrawal Studied et al 27 The preparation andphysico-chemical evaluation of rifam-picinloaded poly-(lactic-co-glycolic)acid(PLGA) nanoparticles as per 32 Factorial Design are presented. PLGA (X1)and PVA (Polyvinyl alcohol) solution (X2) as as tabilizing agent were used asindependent variables where Particle size (PS) (Y1), Entrapment Efficiency (EE)(Y2) and % Drug Release at 12th h (REL)(Y3) were taken as dependant variables.Rifampicin nanoparticles were prepared by multiple emulsion solvent evaporationmethod. The results showed the method as reproducible, easy and efficient isthe entrapment of drug as well as formation of spherical nanoparticles. Effectof polymer concentration was also evaluated with respect to their % drugentrapment efficiency. The in vitro release studies indicated therifampicin-loaded PLGA nanoparticles provide sustained drug release over aperiod of 12h. The optimum batch was R3 which shown particle size 326 nm, 61.70% EE and 57. 50% drug release at 12th h. Infrared spectroscopy analysisrevealed that there was no known chemical interaction between drug and polymer.Hence, this investigation demonstrated the potential of the experimental designin understanding the effect of the formulation variables on the quality ofrifampicin nanoparticles.

4.3   Vikesh Shukla et al 28 Oral route ofadministration have wide acceptance up to 50-60% to total drug forms. Fastdisintegrating drug delivery system has number of advantage such as fasteronset of action, attractive elegance, ease of administration. In this study, anattempt has been made to study compression method, for formulation of fastdisintegrating tablets of Isoniazid and Rifampicin, anti-tubercular drugs inview of enhancing bioavailability. Prior to formulation the pre-compressionparameters were characterized for flow properties and prepared formulationswere evaluated for physico-chemical parameters, X-ray powder crystallography,SEM. All four formulations possessed good disintegration properties with totaldisintegration time of 25 to 40 seconds. The effects of Kollidon CLsuperdisintegrant and process variables on drug release profile anddisintegration property were evaluated and results revealed the better drugrelease with Kollidon CL. All formulations are rapidly disintegrated in oralcavity as well as all formulations possess good anti-tubercular properties. SEMShowed the mechanical strength of the formulations affected the morphologicalchanges after compression. Hence, it is evident from this study that fastdispersible tablets could be a promising delivery system for Isoniazid andRifampicin combination with good mouth feel and improved drug availability withbetter patient compliance.

4.4 VIKESH SHUKLA et al 28 Oral route of administration have wide acceptance up to 50-60%to total drug forms. Fast disintegrating drug delivery system has number ofadvantage such as faster onset of action, attractive elegance, ease ofadministration. In this study, an attempt has been made to study directcompression method, for formulation of fast disintegrating tablets ofRifampicin, an anti-tubercular drug in view of enhancing bioavailability. Theseformulations have sufficient hardness and can be manufactured by commonly usedequipment. Prior to formulation the pre-compression parameters werecharacterized for flow properties and prepared formulations were evaluated forphysico-chemical parameters, X-ray powder crystallography, SEM. All fourformulations possessed good disintegration properties with total disintegrationtime of 25 to 40 seconds. The effects of different superdisintegrants andprocess variables on drug release profile and disintegration property wereevaluated and results revealed the better drug release with differentsuperdisintegrants such as Ac-di sol, Explotab, Kollidon CL and PolyplastadoneXL. All formulations are rapidly disintegrated in oral cavity as well as allformulations possess good antitubercular properties. SEM Showed the mechanicalstrength of the formulations affected the morphological changes after compression.Hence, it is evident from this study that fast dispersible tablets could be apromising delivery system for Rifampicin with good mouth feel and improved drugavailability with better patient compliance.

4.5F.V. Manvi et al29 Oral route of administration have wide acceptanceup to 50-60% to total drug forms. Fast disintegrating drug delivery system hasnumber of advantage such as faster onset of action, attractive elegance, easeof administration, manufacturing, storage and transport. In this study, anattempt has been made to study direct compression method, for formulation offast disintegrating tablets of Isoniazid, an anti-tubercular drug in view ofenhancing bioavailability for the treatment of oral tuberculosis. Theseformulations have sufficient hardness and can be manufactured by commonly usedequipment. Prior to formulation the precompression parameters werecharacterized for flow properties and prepared formulations were evaluated forphysico-chemical parameters, X-ray powder crystallography, Scanning ElectronMicroscopy and anti-tubercular activity. All four formulations possessed gooddisintegration properties with total disintegration time of 25 to 40 seconds.The effects of different superdisintegrants and process variables on drug releaseprofile and disintegration property were evaluated and results revealed thebetter drug release with different superdisintegrants such as Ac-di sol,Explotab, Kollidon CL and Polyplastadone XL. SEM results showed the mechanicalstrength of the formulations affected the morphological changes aftercompression. Hence, it is evident from this study that fast dispersible tabletscould be a promising delivery system for Isoniazid delivery with good mouthfeel and improved drug availability with better patient compliance.

4.6  PatilJ.S.et al30 Orally administered drugs completely absorb onlywhen they show fair solubility in gastric medium and such drugs shows good bioavailability.The solubility and dissolution properties of drugs play an important role inthe process of formulation development.Problem of solubility is a majorchallenge for formulation scientist which can be solved by differenttechnological approaches during the pharmaceutical product development work.Solid dispersion, solvent deposition, micronization are some vital approachesroutinely employed to enhance the solubility of poorly water soluble drugs.Each approach suffers with some limitations and advantages. Amongall,complexation technique has been employed more precisely to improve the aqueoussolubility, dissolution rate, and bioavailability of poorly water solubledrugs. Cyclodextrins, the unique cyclic carbohydrates are successfully utilizedas the potential complexing agents which form inclusion complex with insolubledrugs. A comprehensive literature survey was made collect the rightfulutilization of cyclodextrins as complexing agents and permeation enhancers.Various techniques have been investigated to explain the methods for preparationof inclusion complexes. In the present review, an attempt was made to discussvarious complexation techniques and tried to briefly highlight the potentialapplications, technical and economical limitations associated with theseapproaches.

4.7   A.K. Chakraborty et al 31India is classified along with the sub-Saharan African countries to beamong those with a high burden and the least prospects of a favourable timetrend of the disease as of now (Group IV countries). The average prevalence ofall forms of tuberculosis in India is estimated to be 5.05 per thousand,prevalence of smear-positive cases 2.27 per thousand and average annualincidence of smear-positive cases at 84 per 1,00,000 annually The credibilityand use of the estimates are discussed in detail. Reports on recent studies onthe time trend of the disease from some areas in India, e.g., Chingleputin Tamil Nadu are discussed. They confirm the slow downward trend over a fairlylong period of observation, as in the rural areas around Bangalore. It alsooutlines the serious escalation of disease burden in a tribal population groupin Car Nicobar over a period 1986-2002, and highlights the nature and extent ofthe emerging threats. Some epidemiologists forecast a rise of 20 per cent inincidence in the next 20 yr, for India, with a cumulative rise of 46 millioncases of tuberculosis during that period, largely as a consequence of HIVepidemic. The Governmental efforts at intervention through Revised NationalTuberculosis Control Programme (RNTCP) and at monitoring the epidemiology ofintervention through organizing routine reporting are highlighted, and data arepresented and evaluated on these. RNTCP need to be used as an effectiveinstrument to bring a change in epidemiological situation, through fastexpansion and achievement of global target.

4.8Shrutidevi Agrawal, et al 32 Rifampicin is one of theoldest and most effective chemotherapeutic agents available for the treatmentof tuberculosis but exhibits variable bioavailability from separate and fixeddose combination formulations, which has been identified as a major bottleneckin the effective treatment of tuberculosis. In this investigation,physico-chemical characterization, single dose pharmacokinetic studies and thepermeability of rifampicin under physiological conditions in the rat werestudied to trace the possible reasons for its variable absorption. Rifampicinexhibits very high solubility in acidic and basic pH, corresponding to the pHof the stomach and distal intestine, respectively, whereas it is moderatelysoluble at the jejunal pH. From single-dose pharmacokinetic studies andpermeability characterization, rifampicin is a highly permeable molecule andthus according to BCS, it is a borderline class II drug. This investigation hasruled out the possibility of intrinsic solubility, effective permeability, drugdecomposition, presystemic metabolism and interaction with otherantituberculosis drugs as direct factors responsible for the variablebioavailability of rifampicin. However, it was found that the rate ofdissolution in association with pH and the concentration-dependent absorptionof rifampicin affects the in vivo performance of the dosage forms. Inaddition, this is the first report of methodology for correcting inletconcentration for permeability calculations of a chemically unstable molecule.Copyright © 2005 John Wiley & Sons, Ltd.

4.9 Saranjit Singh et al 32The problem of poor/variable bioavailability of rifampicin, which is shownin particular when the drugs are present in anti-tubercular fixed-dosecombination (FDC) products, is a matter of serious concern. There is apotential of failure of therapy in patients with an active disease. It perhapsalso is a contributory factor towards the increasing resistance toanti-tubercular drugs. Unfortunately, the origin and cause of the problem isnot clearly understood, though GMP and crystalline changes in the drug areinvariably cited as the principal reasons. In this write-up, various probablephysical and/or chemical reasons are critically reviewed. The enhanceddecomposition of rifampicin in the presence of isoniazid in stomach afteringestion is indicated to be the key factor behind the problem. Some simplesolutions offered by the knowledge of the cause are discussed and it isconcluded that there is a need to have a multifaceted approach to handle theproblem.

4.10D. Prabakaran et al 35 Sustained release asymmetricmembrane capsular systems were developed for simultaneous oral delivery ofrifampicin and isoniazid sodium in order to reduce the problems associated withthe multi drug therapy of tuberculosis. Dense semipermeable membrane coatingcapsules were also prepared for the delivery of these drugs by adopting twodifferent filling approaches. In vitro release studies were carried out for bothtypes of systems and the results were compared. Asymmetric membrane capsulesprovided sustained release of rifampicin associated with initial burst release,where isoniazid release rates were comparatively high due to higher aqueoussolubility. Dense semipermeable membrane systems provided controlled release ofboth drugs but were devoid of initial burst release of isoniazid. To overcomethese drawbacks, a modified asymmetric system was developed by addingappropriate amount of hydrophilic polymer mixture with isoniazid. The systemprovided satisfactory sustained release of rifampicin and isoniazid withinitial burst release may be sufficient to achieve minimum effectiveconcentration in blood. In vitro dissolution kinetics of the systems followedfirst order kinetics and statistical analysis of release rate data proved thatmodified asymmetric system was better amongst the developed systems.

5. RESEARCH ENVIASAGED

Thebasic development work encompasses the preformulation work and the subsequentdosage form development

5.1 Preformulation Study37,41,45

Prior to the development of any dosage form with a new or old drugcandidate, it is essential that certain fundamental physical and chemicalproperties of the drug molecule and other derived properties of the drug isdetermined. This information will dictate many of the subsequent events andpossible approaches in formulation development. This first learning phase isknown as preformulation.

5.2. Compatibility Study

For the purpose of compatibility, the drug & excipients are taken infollowing ratios for both drugs. It is kept at,

60° C in open condition for 1 week

40°C/75%RH C for 1 month: Thedrug and excipients kept in clean vials and packed with aluminium foil withsmall holes.

30C/65%RH in closedcondition for 1 month: The drug and excipients kept in clean vials andpacked with rubber closure.


5.2.1. COMPATABILITY STUDY FOR RIFAMPICIN+ISONIAZIDE

SR no

INGREDIENT

RATIO

( 1:1 )

1

Rifampicin- USP

0.25gm

2

Rifampicin+Maize Starch

1:1

3

Rifampicin+Sodium starch glycolateUSP/NF

1:1

4

Rifampicin+Magnesium sterate

1:1

5

Rifampicin +colloidal silicon dioxide IP/LG

1:1

6

Rifampicin+sodium starch

1:1

7

Isoniazide - USP

0.25gm

8

Isoniazide +Maize Starch

1:1

9

Isoniazide +Sodium starch glycolateUSP/NF

1:1

10

Isoniazide +Magnesium sterate

1:1

11

Isoniazide +colloidal silicon dioxide IP/LG

1:1

12

Isoniazide +sodium starch

1:1

 

 


 

Table No. 12

5.3.OBJECTIVE:

To generateinformation useful to the formulator in developing stable and effective dosageforms that can be mass-produced.

Particle sizedetermination29

Particle sizeand surface area are two of the most important properties influencing thedissolution rate of a drug and thus its bioavailability. Particle sizereduction (e.g., micronization) is often utilized to enhance dissolution rate.Small particles present a larger surface area per unit weight to thedissolution media and hence dissolve more rapidly than large particles.

 Particle size and shape also play an extremelyimportant role in the homogeneity of powder blends and then blending of powdersin a mixer. Particle size may also affect the stability of a drug substance, inthat it governs the surface area available for oxidation and stability of adrug substance, in that it governs the surface area available for oxidation andhydrolysis. Surface area is critical for interaction with excipients in tabletdosage forms and can greatly affect stability.

Method:

MalvernMastersizer, which uses the principle of light scattering, determined particlesize of Rifampicin and Isonizide.

5.3.1.Identification

 

1.  UV Spectroscopy

Rifampicin in 0.1NHydrochhrolic acid has one strong peak at 475 nm and Isonizide in 0.1NHydrochloric acid  has one strong peak at254 nm.

UV calibration doneby simultaneous equation,

CX=   A2ay1-A1ay2    /    ax2ay1-ax1ay2

CY  =   A1ax2-A2ax1   /    ax2ay1-ax1ay2

Where

X and Y – Respective drugs

ax1 andax2 – absorptivity of X at λ1 and λ2 respectively

ay1 anday2 – absorptivity of Y at λ1 and λ2 respectively

CX and CY– concentration of X and Y respectively in dilute sample

A1 and A2– absorption of diluted sample at λ1 and λ2 respectively

 

2.  IR Spectroscopy

Infraredspectroscopy (IR spectroscopy) is the subset of spectroscopy that deals withthe infrared region of the electromagnetic spectrum.

For a moleculeto absorb in Infra red ranges, the vibrations or rotations within a moleculemust cause a net change in the dipole moment of the molecule. The alternatingelectrical field of the radiation interacts with fluctuations in the dipolemoment of the molecule. If the frequency of the radiation matches thevibrational frequency of the molecule then radiation will be absorbed, causinga change in the amplitude of molecular vibrational.

The term "infra red" covers the range of the electromagneticspectrum between 0.78 and 1000 mm. In the context of infrared spectroscopy,wavelength is measured in "wave numbers", which have the unit’s cm-1.

Wave number = 1/ wavelength in centimeters

TableNo 13 Three infrared region; near, mid and far infrared

Region

Wavelength range (m)

Wave number range (cm-1)

Near

0.78 - 2.5

12800 - 4000

Middle

2.5 – 50

4000 - 200

Far

50 –1000

200 - 10

  

   The most useful I.R. region lies between4000 – 670 cm-1

 

            For Rifampicin

Theinfrared spectrum of Rifampicin  in a KBrpellet  gives  peaks  at  differentwave         Numbers.

For Isonizide

Theinfrared spectrum of Isonizide in a KBr pellet gives peaks at different wave

Numbers.

3.      Apparent density / Bulk density :

Bulk density orapparent density is defined as the ratio of mass of a powder to the bulkvolume. The bulk density of a powder depends primarily on particle sizedistribution, particle shape, and the tendency of the particles to adhere toone another.

Method:

25 gm of drug(M) was accurately weighed shifted through 20 # sieve and transferred in 100 mLgraduated cylinder. The powder was carefully leveled without compacting, andthe unsettled apparent volume (V0) was taken. The apparent bulkdensity in g/mL was calculated by the following formula:                                  

4.      Tapped bulk density :                                                                                  

 25 gm of drug was accurately weighed andsifted through 20-mesh sieve and transferred in 100 mL graduated cylinder. Thecylinder containing the sample was mechanically tapped by raising the cylinderand allowing it to drop under its own weight using mechanically tapped densitytester that provides a fixed drop of 14± 2 mm at a nominal rate of 300 dropsper minute. The cylinder was tapped for 500 times initially and the tappedvolume (V1) was measured to the nearest graduated units. The tappingwas repeated for an additional 750 times and the tapped volume (V2)was measured to the nearest graduated units. If the difference between the twovolume is less than 2 % then final the volume (V2).

                                                     Weight of the Blend

                        TD =                                      

                                                Tapped Volume of the packing

5. Hausner ratio :

Hausner ratiogives an idea regarding the flow of the blend. It is the ratio of tappeddensity to the apparent density. Hausner ratio was calculated as:  

                                                           

                      HR= Tableno 14 Hausner Ratio

                                       

                                Hausner Ratio                    

  Flow 

                  1 – 1.11

Excellent

1.12 - 1.18

Good

1.26 – 1.34

Poor

6.   Compressibilityindex31-32:

Thecompressibility index measures of the propensity of powder to be compressed.The packing ability of drug was evaluated from change in volume, which is dueto rearrangement of packing occurring during tapping. It is indicated as Carr’scompressibility index (CI) and can be calculated as follows:

                                               CI% =        Tapped density– Apparent density                       
                                                                          

                                                                           Apparent density

 
 

Table No. 15 Compressibility index

Compressibility index

Flow

Less than 10

Excellent

11-15

Good

16-20

Fair

26-30

Poor

28-35

Poor

35-38

Very poor

40 +

Extremely poor

7.  Active pharmaceutical ingredient calculation

The quantity of API to be dispensed indone based on assay and moisture content by using following formula:                               

8.  Conversion factor:

 Thisconversion factor is taken into consideration because the assay of candidatedrug salt is reported in the certificate of analysis and the complete waterdetermination by KF (bound and unbound).

5.4.Finished productparameter:42

1.  In -vitro dissolution studies:

The release rate ofRifampicin and Isonizide from capsule was determined using United StatesPharmacopeia (USP) Dissolution Testing Apparatus I (Basket). The dissolutionmedium was 0.1N Hydrochloric acid, the volume being 900 ml. The temperature wasmaintained at 37±0.5°C.The rotation speed was 100 rpm. A sample (10 ml) of the solution was withdrawnfrom the dissolution apparatus at predetermined time intervals and the sampleswere replaced with fresh dissolution medium. The samples were filtered througha 0.45μ membrane filter anddiluted to a suitable concentration with dissolution medium. Absorbance of these solutions was measured at 475 nm &254 nm using UV/Visible double-beam spectrophotometer. Cumulative percentagedrug release was calculated using an equation obtained from a standard curve

 2.  Assay of Rifampicin and Isonizide  (by HPLC) :

TableNo. 16 Reagents

Disodium hydrogen orthophosphate

:

HPLC Grade

Ortho phosphoric acid

:

 HPLCGrade

Acetonitrial

:

HPLC Grade

Water

:

MILL PORE

Buffersolution PH 6.8 :

Dissolve1.4 g of Disodium hydrogen orthophosphate anhydrous in 1000 ml of purifiedwater ,adjust to 6.8 – 0.05 with orthophosphoric acid .

Mobile phaseA: Prepare a filtered and degassed mixture of Buffer solution:Acetonitrile (96:4)

Mobile phaseB:  Prepare a filtered and degassed mixture ofBuffer solution:Acetonitrile (45:55)

Diluent preparation: Prepare a mixture of Acetonitrial: Water (80:20 v/v)

Table No 17 Chromatographicconditions

Column

:

250- 4.6, 5mm base deactivated C18 packing

Column temp.

:

30°C

Sample temp.

:

15°C

Wavelength

:

238 nm

Injection volume

:

20 mL

Flow rate

:

1.5 mL/min.

Run time

:

15 minutes.

Table No 18 Gradient programmed

                      Time (min)        

                                            Conc of A(%)

                               Conc of B (%)

                                    Elution

0.01

100

0

Equilibration

0-5

100

0

Isocratic

5-6

100-0

0-100

Linear gradiant

6-15

0

100

Isocratic

Preparation of standard solution:

weighaccurately about 60mg of Rifampicin ws ,40mg of Isoniazide ws into a 500 mlvolumetric flask ,dissolve in 20ml of methanol for 5-10 minutes to dissolve,dilute up to the mark with buffer solution mixture.

                   

Preparation of test solution:

At the end of testrun ,withdrawn a 25 ml aliquot ,and filter and discarding first 10 ml ,of thefiltrate .allow to cool for about 10 min .and transfer 5.0ml of the filtrateand 20.0 ml of the phosphate buffer solution to 100 ml volumetric flask .dilutewith the water to volume and mixed.

 Procedure:

Filtered the standard and test preparation through 0.45 mm membranefilter. Inject standard in the replicate & test in duplicate and record thechromatogram calculate the system sutability parameter from standardchromatogram

Evaluation ofsystem suitability:

 The column efficiencydetermined for the Rifampicin  &  Isonizide peak obtained from standardpreparation should be not less than 50000 and 6000 theoretical platesrespectively.

Tailing factor for Rifampicin & Isoniazide peakobtained from standard preparation should be in between 0.8 to 2.0

The percentage relative standarddeviation for Rifampicin &Isoniazidepeak area counts from five replicate injections of standard solution should benot more than 2.0 %.The retention time of peaks Rifampicin &Isoniazide are about 2.6 minutes & 1.ominutes respectively.

Calculation: Calculate % Assay of Rifampicin &Isoniazide by using the following formula-

For Rifampicin :

AT

 

WS

 

DT

 

P

 

 

-----

x

-----

x

-----

x

-----

x

100

AS

 

DS

 

LC

 

100

 

 

 

 

 

 

Where,

AT        = Absorbance of test preparation  

AS        = Absorbsnce of standard preparation

WS       = Weight of the standard mg

P           = Percentage potencyof  the Rifampicin  workingstandard, as Rifampicin on asis basis.

AW       = Average Weight in mg

DS         = Dilution of standard preparation .

DT         = Dilution of test preparation.

LC         = Label claim

 

 For Isoniazide :

AT

 

WS

 

DT

 

P

 

 

-----

x

-----

x

-----

x

-----

x

100

AS

 

DS

 

LC

 

100

 

 

 

Where,

AT        = Absorbance of test preparation  

AS        = Absorbance of standard preparation

WS       = Weight of the standard mg

P           = Percentage potencyof  the Isoniazid working standard, as Isoniazid on as is basis.

AW       = Average Weight in mg

DS         = Dilution of standard preparation .

DT         = Dilution of test preparation.

LC         = Label claim

  1. Dissolution of Rifampicin and Isoniazide by (UV&HPLC) :

Table No. 19 Reagents

Dibasic potassium phosphate

:

HPLC Grade

Monobasic potassium phosphate

:

HPLC Grade

0.1 N Hydrochloric acid

:

HPLC Grade

Water

:

Milli-Q / HPLC Grade

 

Dissolutionparameters

Medium

:

0.1 N Hydrochloric acid

Volume

:

900 mL

Apparatus

:

USP type-I (Basket)

RPM

:

100 rpm

Temperature

:

37 °C ±0.5

Time

:

45 minutes

 

Dissolutionmedium 0.1 N Hydrochloric acid placed in volumetric flsk .

 Phosphate buffer solution : dissolved 15.3 ofdibasic potassium phosphate and 80.0g of monobasic potassium phosphate into a1-lit volumetric flask ,mix and dilute the water to volume & mix.  Filter through 0.45-µ-membrane filter.

Mobile phase  : prepared filter and degassed mixture ofwater ,phosphate buffer solution ,and methanol (850:100:50).Make necessaryadjustment .

                            Table No.20 Chromatographic conditions

Column

:

Peerless basic C18, (4.0 x 300) mm , 10-µm

Column temp.

:

30°C

Sample temp.

:

Ambient

Wavelength

:

254nm

Injection volume

:

10 mL

Flow rate

:

1.5 mL/min.

Run time

:

15 minutes.


Table No. 21 Gradient programme

Time (min)

Conc of A(%)

Conc of B (%)

Elution

0.01

100

0

Equilibration

0-5

100

0

Isocratic

5-6

100-0

0-100

Linear gradiant

6-15

0

100

Isocratic







 

Preparation of standard solution:

Isoniazid standard solution : accurately weigh about 66 mg ofisoniazid WS into a 100 ml volumetric flask .dissolve in and dilute with 0.1 NHydrochloric acid to volume flask.

Standard stock solution  :accurately weigh of about 66mg of rifampicin WS into a 200 ml volumetric flask.And dissolved in 10 ml of 0.1N Hydrochloric acid & mix added 50 ml ofisoniazide standard solution and dilute with 0.1 N Hydrochloric acid to vol andmix.

Standard solution :- 

At the end of thetest run ,transfer a 5.0ml aliquot of the standard stock solution and 10.0ml ofphosphate buffer solution to a 50 ml volumwtric flask . dilute with the waterto volume and mixed .

Preparation of test solution:

At the end of testrun ,withdrawn a 25 ml aliquot ,and filter and discarding first 10 ml ,of thefiltrate .allow to cool for about 10 min .and transfer 5.0ml of the filtrateand 20.0 ml of the phosphate buffer solution to 100 ml volumetric flask .dilutewith the water to volume and mixed.

Procedure:

Filteredthe standard and test preparation through 0.45 mm membrane filter. Injectstandard in the replicate & test in duplicate and record the chromatogramcalculate the system sutability parameter from standard chromatogram.                                                                                                                                                                               

 

Evaluationof system suitability:

The column efficiency determinedfor the Rifampicin  &  Isonizide peak obtained from standardpreparation should be not less than 50000 and 6000 theoretical platesrespectively.

Tailing factor for Rifampicin & Isoniazide peakobtained from standard preparation should be in between 0.8 to 2.0

The percentage relative standarddeviation for Rifampicin&Isoniazide peak area counts from five replicate injections of standardsolution should be not more than 2.0 %.The retention time of peaks Rifampicin &Isoniazide are about2.6 minutes & 1.o minutes respectively.

Calculation % dissolution of RIFA & INH :

AT

 

WS

 

DT

 

P

 

-----

x

-----

x

-----

x

-----

x

100

AS

 

DS

 

LC

 

100

 

 

 

                            

              

 Where,

AT        = Absorbance of test preparation  

AS        = Absorbance of standard preparation

WS       = Weight of the standard mg

P           = Percentage potencyof the working standard,

AW       = Average Weight in mg

DS         = Dilution of standard preparation .

DT         = Dilution of test preparation.

LC         = Label claim

5.4.Stability study :55,56

Introduction:

In any rationaldesign and evaluation of dosage forms for drugs, the stability of the activecomponent must be a major criterion in determining their acceptance orrejection.

Stability of a drugcan be defined as the time from the date of manufacture and the packaging ofthe formulation, until its chemical or biological activity is not less than apredetermined level of labeled potency and its physical characteristics havenot changed appreciably or deleteriously.

6.5.Objective of the study:

The purpose ofstability testing is to provide evidence on how the quality of a drug substanceor drug product varies with time under the influence of a variety ofenvironmental factors such as temperature, humidity and light, enablingrecommended storage conditions, re-test periods and shelf- lives.

Generally, theobservation of the rate at which the product degrades under normal roomtemperature requires a long time. To avoid this undesirable delay, theprinciples of accelerated stability studies are adopted.

The InternationalConference on Harmonization (ICH) Guidelines titled “stability testing of NewDrug substance and products” (QIA) describes the stability test requirementsfor drug registration applications in the European Union, Japan and the United States of America.

ICH specifies thelength of study and storage conditions.

ICH guidelines for stability study34-35

Study Storagecondition Time period

Tableno 22 Time period of storage condition

Study

Storage condition

Time period

Long term

25°C±2°C/60%RH±5 RH or

30°C±2°C/65%RH±5%RH

24 month

Intermediate

30°C±2°C/65%RH±5%RH

12 month

Accelerated

40°C±2°C/75%RH±5%RH

6 month

 

* It is up to theapplicant to decide whether long term stability study are performed at25°C±2°C/60%RH±5%RH or 30°C±2°C/65%RH±5%RH.

** If30°C±2°C/65%RH±5%RH is a long term condition there is no intermediate condition

If significantchanges occur at these stress conditions, then the formulation should be testedat an intermediate condition that is 30°C/65% RH.

In the present workstability study was carried out for the optimized formulation for followingcondition and time period, at 40°C/75%RH for 6 month and 25°C±2°C/60%RH±5% upto 24 month.

 

After time period of every month sample was collected andanalysis is carried out for

Following:

1.     Appearance

2.     Dissolution

3.     Assay

4.     Relatedsubstances

5.     Disintegrationtime

 

5.6 Drug profile ofthe Rifampicin :45,46

 

 Structure of the Rifampicin

Figure no 3.Structure of the Rifampicin

  

 Table no 23 Drug profile of Rifampicin .

Drug

                                           Rifampicin.

Official status

Official in I.P./U.S.P.

Chemical name

7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,27,29-pentahydroxy-11-methoxy-3,7,12,14,16,18,22-heptamethyl-26-{(E)-[(4-methylpiperazin-1-yl)imino]methyl}-6,23-dioxo-8,30-dioxa-24-azatetracyclo[23.3.1.14,7.05,28]triaconta-1(28),2,4,9,19,21,25(29),26-octaen-13-yl acetate

CAS No

13292-46-1

Molecular formula

C43H58N4O12

Molecular weight

822.94 g/mol

Category

Antitubercular  agent

Description:

Red coloured powder

Melting point

183–188 °C (361–370 °F)

Solubility

Soluble in water.

Calcium content

3.00-5.00%

Assay by HPLC:

97.0% to 102.0% w/w

Pka

4.46

 

5.7 Drug profile for Isoniazide:

 Structure of Isoniazide

Figure no 4 Structure of Isoniazide

 

Table no 24 Drug profile for Isoniazide

 

Drug

 

Isoniazide

Official status

Official in I.P. and U.S.P.

Molecular formula

C6H7N3O

Chemical name

Isonicotinohydrazide

CAS No

54-85-3

Molecular weight

137.139 g/mol

Category

Antitubuarcular antibiotics

Description

A white or almost white, crystalline powder

Melting point

90-120c

Solubility

Very soluble in methylene chloride, slightly soluble in alcohol, practically insoluble in water.

Assay by HPLC

NLT 98.0% and NMT 102.0%

FormulationDevelopment

Development of aformulation starts with the evaluation of the branded marketed product followedby compatibility studies, selection of process and equipments and lastly thefeasibility trails towards a stable bioequivalent product.

In order to develop a capsuleformulation of antitubercular agents; initialrequirement was to choose a suitable process.

Separate batches for theRifampic and Isoniazide were formulated by using different disintegrants,surfactant and binders, from this, following formulations have been selectedwhich gave best results.

MANUFACTURING PROCESS FLOW

Brief manufacturing procedure for R-cinex capsule :

1

Check and verified AR number of all dispensed material and also checked their weight.

2

Sifted Rifampicin through 14 # s.s sieve manually and collected double polythene bag

3.

Collected and transferred of shifted Rifampicin of step 2 into a s.s container and added liquid paraffin to it then mixed manually sifted it through 14# s.s sieve  manually and collected in a separate polythene bag .

4.

Sifted maize starch and colloidal silicon dioxide through 40 # s.s sieve manually and collected in a separate polythene bag

5.

Sifted Isoniazid through 14# s.s sieve manually and collected in separate polythene bag

6.

BLENDING: Loaded the material of step 2 into octagonal blender and then added material of step 3 into it then mixed for 1 min.

7.

Transferred the material of step 4 into octagonal blender containing the material of step 6 and mixed it for 1 min.

8.

Then again transferred the material of step 5 into octagonal blender congaing material of step 7 and mixed it for 1 min

9

Unloaded the material of step 8 and sifted it through 20# s.s. sieve this was collected separately in double polythene bag.

10

The retained sample from sieving in step 9 was passed through 14 # sieve and collected in separate polythene bag .

11

Again loaded the material of step 9 and step 10 in octagonal blender and mixed it for 1 min.

12.

Sifted the talc and Sodium starch glycolate through 40# sieve manually and collected in double polythene bag.

13.

Transferred the sifted extragranular material of step 12 into octagonal blender containg the material step 11and mixed for 10 min .

14.

Sifted Magnesium sterate through 40 # s.s sieve and collected in double polythene bag .

15

Transferred the sifted Magnesium sterate of step 14 in to octagonal blender containing material of step 13 and mixed for 1 min

16

Unload the material of step 15 in separate double polythene bag

17.

 Half qty of Capsule were thereby filled manually in which two sample were taken and half qty were filled PAM Capsule fill machine.

18

After collection sample were sent to Q.C analysis.

Conclusion:

It was concluded from the observations of thepreformulation studies that there was no change in the physical attributesobserved in 25°+ 2°C/60+5%RH & 40°+ 2°C/75+5%RH. Moreover, the stability study of the developedformulation, would ascertain the same. The definitive ratios ofdisintegrant/binding agents were selected based on the same.

6.2 Particle size analysis

Sizecharacterization during the preformulation studies is extremely important.Dissolution depends largely on the particle size especially for the drugs,which are poorly soluble. With decreasing particle size the surface areaincreases and resultantly an increase in the dissolution or the drug release.Hence, it is desirable and mandatory to establish the particle size range thatneeds to be used for formulation.

Though Rifampicinis insoluble drug, the effect of particle size was studied to ascertainno change in chemical attributes on reducing particle size. Theeffect of particle size was also studied during the formulation development. Itwas observed that when formulations with different particle size as shown inthe table below were evaluated in the drug product, the similarity in thedissolution profile eliminated any significant role of particle size.


 

Sr no.

Batch no.

D (0.9)

D (0.5)

D (0.1)

1

9142A

21.004

10.842

5.075

 Particle size analysis by Malvern Mastersizer for Rifampicin

 

Figure No. 7  Particle size analysis by Malvern Mastersizerfor Rifampicin

 

 

TableNo. 43 Particle size analysis by Malvern Mastersizer.

 

Sr. no.

Batch no.

D (0.9)

D (0.5)

D (0.1)

1

9711D

43.86

22.34

6.725

 

6.3 Sieve analysis data of Rifampicin:

 

Sr No.

Physical characteristic of Rifampicin

Finding

1

Untapped bulk density

0.56

2

Tapped density(200 tapping)

0.72

3

Sieve analysis 100 gm sample

 

4

Total retention on 12# sieve (%)

NIL

5

Total retention on 20# sieve (%)

25.00

6

Total retention on 40# sieve (%)

77.20

7

Total retention on 60# sieve (%)

81.90

8

Total retention on 100 # sieve%

84.54

              TableNo. 44

6.4Sieve analysis data for Isoniazid :

                                             

Sr No.

Physical characteristic of Rifampicin

Finding

1

Untapped bulk density

0.18

2

Tapped density(200 tapping)

0.35

3

Sieve analysis 100 gm sample

 

4

Total retention on 12# sieve (%)

NIL

5

Total retention on 20# sieve (%)

52.00

6

Total retention on 40# sieve (%)

70.20

7

Total retention on 60# sieve (%)

80.90

8

Total retention on 100 # sieve%

90.00

                                                                                                 Table No. 45

 

IDENTIFICATION:43

The calibration curve was developed for concentration rangeof 2.2 μg/ml to 17.6 μg/ml. Theabsorbance was measured at 475 nm using dissolution medium as a blank.

The values ofabsorbance of different concentrations of drug in 0.1NHCL are given.

Concentrationand absorbance for Rifampicin

 

S. No.

Concentration (μg/ml)

Absorbance

1

2.2

0.083

2

3.3

0.122

3

4.4

0.164

4

5.5

0.206

5

8.8

0.319

6

11

0.399

7

13.2

0.476

8

17.6

0.641

 

 

 

Fig.No-8standard curve for rifampicin

The calibration curve was developed for concentration rangeof 1.6 μg/ml to 24 μg/ml. Theabsorbance was measured at 254 nm using dissolution media as a blank.

The values of absorbanceof different concentrations of drug in 0.1NHCL are given in the

Table no: 6.6

Concentration andabsorbance for Isoniazid

 

S. No

Concentration ((μg/ml)

Absorbance

1

1.6

0.154

2

3.2

0.295

3

9.6

0.443

4

12.8

0.595

5

16

0.739

6

24

0.904

          Figno-9 standard curve for Isoniazide

IR Spectroscopy

For Rifampicin

The infrared spectrumof Rifampicin in a KBr pellet gives peaks at different wave numbers listed intable no.40

 IR Spectra for Rifampicin


 

FigureNo 10  IR Spectra for Rifampicin

  

Sr. No.

Wave number

cm -1

Functional group

1

3666.17

O-H Stretch

2

1900.71

C=O Stretch

3

1650.93

C=N

4

1317.02

C-O Stretch

5

883.84

C-H

 

 

 

 

 

 

 




Table No 46 Wave number for Rifampicin

                                                             

For Isoniazide:

The infrared spectrumof Isoniazide in a KBr pellet gives peaks at different wave numbers listed in table no.41

IR Spectra for Isoniazide

FigureNo 11 IR Spectra for Isoniazide

Table No 47 Wavenumber for Isoniazide

Sr. No.

Wave number

cm -1

Functional group

  1

3434.72

C=O Stretch(2v)

2

3053.88

= N-H

3

2984.94

C-H Stretching

4

1287.13

O-H Bending

5

1013.9

C-C Stretch

6

860.07

C-H Stretch

                                                         

            

 

             

 

 

 

 

 

 

 

CONCLUSION:                                                                                                                                 

  The infrared absorption spectrum in potassium bromide (KBr) exhibitsmaxima only at the same wavelength as that of a similar preparation of workingstandard. I.R match with the reference standardavailable. Thus the drug was authentic. This confirms the identificationof the both API.

6.6 Stability batches results:

7.7 Capsules kept for stability studies wereexamined. The color  of  the formulation,  i.e. F-12 wassimilar before and after stability studies. Shell texture of the formulationpacked in PVC/PVDC (clear) Aluminum Blister pack had no change at 40°C/75%RH (±20 C/±5RH) after three months. This indicated that thecapsules had no effect of moisture from the environment in PVC/PVDC (clear)Aluminum Blister pack.

Drug Content 

Drug content wasdetermined at every specified interval of time. The drug content was calculatedby HPLC method.

Table No 77 Stability results

Sr No

Specification

Initial

1 month

2 month

3 month

1

 

 

 

Description                                                                                                                  

Shell-scarlet orange coloured “00” size hard gelatine capsule with

R-CINEX.LUPIN LOGO LUPIN

Contents: Mottled brick red granular powder/slug.

Complies

Complies

Complies

2

Assay

i.        Rifampicin

ii.      Isoniazid

 

       100.11%

       101.20%

 

89.56%

97.80%

 

98.7%

86.12%

 

86.54%

98.90%

3

Dissolution of Rifampicin

102.0%

 

97%

99%

99%

4

Dissolution of Isoniazid

95.00%

90%

80%

83%

 

6.8Chromatographs of samples used for calculating the drug content by HPLC system

The following were the one month and threemonths stability samples which were analyzed on HPLC to find out the drugcontent.

 

Conclusion:

It is concluded fromthe stability result, that the appearance, assay and release of both drug arein the specifications.

Theresults of the drug content calculated at the end of three months showed F-12formulation by chromatograms there was no significantchange in the drug content. It also showed that the drug was stable inpresence of excipient kept at elevated temperature and humidity; hence weconcluded that formulation F12 wasmore stable.

7.0 Summary:

The F-12 Formulation was characterized for various properties of thedosage forms like assay, related substances, dissolution and other physicalproperties. The experimental formulation was found to be pharmaceuticalequivalent  to other marketed dosageform.To ensure these systematic studies were carried viz. API evaluation,formulation development and stability studies. The particle size of Rifampicin was optimized by usingthe Malvern Mastersizer.

The release  ofthe Rifampicin improved by  adding  the Maize  starch as  Disintegrant.

The release of Rifampicin improves because of micronizedform of the drug i.e. 20 micron. And also by sodium starch glycolate as anintra granular and extra granular as disintegrant.

The release of Rifampicin and Isoniazid also improved byusing Sodium laurel sulphate  as a Wettingagent.

Also investigation of various factor affectingencapsulation on In-Cap Automatic capsule filling machine.

·        Influence of pin position on fill weight andweight variation ..

·        Influence of powder bed height on fill weight .

·        Powder characteristic and capsule filling .

The Final trial( F12) was packed inPVC/PVDC blister packing and kept it for at 40°C/75%RH±5%  for 6 month and25°C±2°C/60%RH±5% up to 24 month as per the ICH guidelines but I was kept it at40°C/75%RH±5%  for 3 month.

Therelease of drugs from stability batch of 1 month and 2 month conducted on HPLCwas found to be satisfactory result ..

Itwas observed that F-12 batch had better solubility and dissolution rate .


7.1 Conclusion:

      From the results obtained, following conclusions were drawn

·        The Drug excipients compatibility studies showedthat the excipient used in final formulation had no interaction with the drug.The excipient were compatible with the API.

·        Evaluation of physicochemical parameters likeshape size, moisture content, dissolution and assay indicated that the capsulewere mechanically stable and complied with necessary pharmacopoeial as well asdesired specification.

·        The release rate of the Rifampicin was improvedas compared to the previous trial batch .

·        The stability testing of finalized batch ataccelerated conditions reveled no significant change with respect to description;assay and dissolution thus indicate the stability of the product.

General considerationfor encapsulating on the in cap:

·     Tamping pin should be adjusted in descendingorder with pin #1 set at relatively higher position compared with pin#4.This will reduce the weightvariation and increases the fill weight .

·     The capsule size and pin setting should beselected such that required powder can filled as plug.

      It was concluded that the process adoptedfor the manufacturing provides a product complied with all the predeterminedspecifications and quality characteristics. The process would imbibereproducibility and robustness in the formulation.

7.2 Future scope:

     Thus result of thecurrent study  clearly indicate, apromising potential of the fixed dose combination of Rfampicin and Isoniazid asan alternative to the conventional dosage form. However, further clinical studiesare needed to assess the utility of this system for patient suffering from T.B.Fix dose combination capsule of Rifampicin and Isoniazid have good potential todevelop into commercial product .

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ABSTRACT

The present investigation deals with development of Fixe dosecombination capsules of Rifampicin and Isoniazide  to produce the intended benefits. Fix dosecombination  capsules of Rifampicin andIsoniazide were prepared using surfactants  sodium laurel sulphate , and Maize starchusing the direct filling  method. The capsulesprepared were evaluated for thickness, uniformity of weight, contentuniformity, water absortion ratio, wetting time, in vitro disintegration time, in vitro drug release and assay by high performanceliquid chromatography. The formulation disintegrated in vitro  within 2 to5 minAlmost 100% of drug was released from all formulations within 45 min. Batch F12shows disintegration time 3min 20 sec. Stability studies of the capsules at40±2 o /75%±5% RH for 1 month showed Non significant drug loss. Theformulation containing combination of Sodium Laurel Sulphate  and Maize starch was found to give the bestresults. Apart from fulfilling all official and other specifications, the capsulesexhibited higher rate of release.

Keywords: Directfilling, in vitro Disintegrationtime, fix dose combination, Rifampicin, Isoniazide, wetting time.

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