CO-Processing of Tablet Manufacturing Process

Introduction
Co-processing is another way that new excipients are coming to market without undergoing the rigorous safety testing of a completely new chemical 19. It can be defined as combining two or more established excipients by an appropriate process11. Co-processing of excipients could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components. The main aim of co-processing is to obtain a product with added value related to the ratio of its functionality/price. Development of co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion, selection of
preparation method to get optimized product with desired physico-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. An excipient of reasonable price has to be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components.

Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them within minigranules. Segregation is diminished by adhesion of the actives on the porous particles making process validation and in process control easy and reliable20. The randomized embedding of the components in special minigranules minimizes their anisotropic behaviour. So, deformation can occur along any plane and multiple clean surfaces are formed during the compaction process. Thus, the use of the co-processed excipient combines the advantages of wet granulation with direct compression20. The use of one-body components is justified if it results in a potentiation of the functionalities over that of the mere dry blend of the components prepared by gravity mixture. This synergistic effect should improve the quality of the tablet equally in all aspects ranging from hardness to dissolution and/or stability.

Excipient mixtures in co-processing are produced to make use of the advantages of each component and to overcome specific disadvantages, if any. Most important characteristics are the binding and blending properties of the co-processed excipients, which must be better than those of a physical mixture of the starting materials. Cost is another factor to be considered in the selection of co-processed product.

Major limitation of co-processed excipient mixture is that the ratio of the excipients in a mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the API and the dose per tablet under development18. Coprocessed adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination fillerbinder will not be accepted by the pharmaceutical industry until it exhibits significant advantages in the tablet compaction when compared to the physical mixtures of the excipients. Although the spray-crystallized dextrose-maltose (Emdex) and compressible sugar are co-processed products, they are commonly considered as single components and are official in USP/NF. Table 4 shows examples of co-processed directly compressible adjuvants.

Need for directly compressible co-processed excipients

The reasons driving the search for new excipients are:
1.    The growing popularity of the direct-compression process and a demand for an ideal filler--binder that can substitute two or more excipients
2.    Increasing tablet machine speed, which require excipients to maintain good compressibility and low weight variation even at short dwell times
3.    Shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose (MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of agglomeration'
4.    The lack of excipients that address the needs of specific patients such as those with diabetes, hypertension, and lactose and sorbitol sensitivity
5.    To develop the ability of excipients to modulate the solubility, permeability, or stability of drug molecules and to increase the performance of Excipients to address issues such as disintegration, dissolution, and bioavailability.

The development of new excipients to date has been market driven (i.e. excipients are developed in response to market demand) and has not seen much activity as shown by the fact that, for the past many years, not a single new chemical excipient has been introduced into the market. The primary reason for this lack of new chemical excipients is the relatively high cost involved in excipient discovery and development. However, with the increasing number of new drug moieties with varying physicochemical and stability properties, there is growing pressure on formulators to search for new excipients to achieve the desired set of functionalities. Development of multi-functional co-processed excipients should significantly carry out the continued popularity of solid dosage forms and increase performance in the direct-compression technology.

Table 4: Co-processed directly compressible excipients

Brand Name	Adjutants	Manufacturer, Country
Cellactose	MCC, Lactose	Meggle, Germany.
Xylitab	Xylitol, Na CMC	Meggle, Germany.
Ludipress	Lactose, PVP, Crospovidone	BASF, Germany.
Starlac	Lactose, Maize starch	Roquette, France.
Pharmatose DLC 40	Anhydrous lactose, lacitol	DMV, Netherlands.
Avicel CE 15	MCC, Guar Gum	FMC, USA.
Celocol	MCC, Calcium phosphate	FMC, USA.
Prosolv	MCC, Colloidal Silica	Penwest.
Di-pac	Sucrose, Dextrin	American sugar, USA.
Advantose FS 95	Fructose, starch	SPI polysol, France.
Advantose 100	Maltose	SPI polysol, France.
Barcoft CS 90	Calcium carbonate,Starch	SPI polysol, France.
Barcoft premix St.	Al-hydroxide,Mg-hydroxide, Sorbitol	SPI polysol, France.
Plasdone S-630	Vinyl acetate, vinyl pyrrolidone	ISP. USA.
Carbofarma G10	Calcium Carbonate	Resins industries, Argentina.
Carbofarma G11	Maltodextrin	Resins industries, Argentina.

co processing of pharmaceutical excipients
Nowadays, co-processing is a much broader platform for the manipulation of excipients' functionality and is the commercially utilized method for the preparation of directly compressible excipients. It can be defined as combining two or more established excipients by an appropriate process.' Co-processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvements as well as to mask the undesirable properties of individual excipients.

Development of a co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion, selection of the preparation method to get an optimized product with desired physicochemical parameters, and it ends with minimizing avoidance with batch¬ to-batch variations (Figure 1).

An excipient of reasonable price has to be combined with the optimal amount of a functional Material in order to obtain an integrated product, with superior functionality rather than the simple mixture of components. The use of one-body components is justified if it results in a potentiating of the functionalities over that of the dry blend of the components prepared by gravity mixture, This synergistic effect should improve the quality of the tablet equally aspects ranging from hardness to dissolution and/or stability.