Creating new possibilities
By Ashok Patel, Ph.D.
“Formulation development is all about playing with your excipients.” This is one phrase that all formulators will agree upon. Excipients are not Active Pharmaceutical Ingredients (APIs); they don’t show any pharmacological effects or treat any medical conditions. But their inclusion in a formulation leads to development of dosage forms that delivers the drug in effective and desired format. Formulation development per se involves modulation of levels of various excipients with respect to the dose of the drug.
Almost 90% of formulations available in the market are solid oral forms, with tablet forming the main bulk of it. Of late there has been a sea change in adapting processes for tablet manufacturing, with most formulators opting for direct compression as the first choice. More emphasis has been put on developing formulas that support tablet manufacturing on high-speed machinery. Also, there has been a drift in the thought process among formulators, as formulas with a minimum number of components are finalized to prevent scale-up issues. Moreover, new tablet formats like Orally Disintegrating Tablets (ODTs) are gaining popularity these days as they carry the promise of extending the market lifespan of the drug.
The recent interest in demanding manufacturing processes and the focus on alternative delivery systems has led to increased demand of a range of specialty excipients collectively known as multifunctional excipients.
Multifunctional excipients are a class of excipients that includes pre-processed and co-processed excipients that provide added functionalities to the formulation (for example, Silicified Micro-Crystalline Cellulose, which is a processed combination of MCC and colloidal silicon dioxide). These functionalities include flowability, compressibility, particle size distribution, shape, porosity, etc. The term multifunctional excipient is also extended to products that serve multiple roles in the formulation (for example, Ludipress, which is co-processed product containing lactose, Kollidon and Kollidon-CL, serves the role of DC diluent with binder and disintegrant properties).
How is Multifunctionality Achieved?
Multifunctional excipients can be obtained by developing a new excipient (such as cross-linked polymers) or by developing new grades of existing excipients; modification in the processing leads to changes in the particle size distribution, particle shape and morphology and porosity. Traditionally, industry stays away from developing a new excipient altogether, due to the cost involved and problems faced in getting regulatory approvals. Changing the manufacturing process of an excipient along with addition of minor amount of another known excipient results in a product that has enhanced physical characteristics leading to added functionality. Combining known excipients at sub-particle level (also known as co-processing) leads to excipients with modified properties like enhanced surface area, increased porosity, enhanced compressibility, good flowability, etc. Co-processed excipients are also suitable for direct compression and thus help in simplification of tablet manufacturing. The reason for enhanced compressibility can be drawn from the fact that most of the co-processed excipients principally consists of a large amount of brittle material and a smaller amount of plastic material. Thus, a co-processed material displays the property, which is a combination of plasticity as well as brittleness.
Development of multifunctional excipients by co-processing involves following steps:
- Selection of parent excipients based on the physical characteristics and functionalities desired in the final product.
- Selecting the level and proportion of component excipients based on the functionalities required in final product.
- Processing of the excipients within the optimum particle size range.
- Co-drying the mixture of excipients using a suitable method such as spray drying or freeze-drying.
There are also instances where pre-processing can lead to product with added functionality (for example, preprocessed partially pregelatinized starches result in better control of particle size distribution, which ultimately leads to lesser dust generation during tabletting and improvised flow of material). However, achieving multifunctionality through preprocessing is not too popular, as the functionality of the excipient can be improved only to a certain extent because of limited number of modifications possible.
From a regulatory perspective, co-processed excipients are not ideally considered as new excipients in terms of safety assessment. As per the FDA guidance, a co-processed excipient is considered GRAS (Generally Recognized as Safe) if the component excipients used in its processing are also GRAS, provided there is no chemical modification during the processing. Hence, these excipients generally don’t require additional toxicological studies.
Applications and Benefits of Multifunctional excipients
Improvised flow: Co-processing of excipient with controlled particle size distribution and particle morphology results in product with superior flow. This has much to do with the spherical shape and even surfaces of the co-processed particles. The improved flowability of the material in turn helps decrease the weight variation problem encountered during the tabletting of a DC formula. This is advantageous especially when working on high-speed machinery.
|Advantose FS 95||Fructose, starch||SPI Pharma||Good flow, high compressibility and taste-masking due to the inherent sweetness of fructose|
|Avicel CE-15||MCC, Guar gum||FMC Corp.||Less grittiness, reduced tooth packing and creamier mouthfeel|
|Cellactose||Lactose, Cellulose||Meggle||High compressibility and good mouthfeel|
|F-MELT||–||Fuji Chemicals||High compressibility, good flow and tailor-made for ODTs|
|Formaxx||Calcium carbonate, Sorbitol||Merck||High compressibility, good flow, superior compaction at low compression force|
|Ludiflash||Mannitol, Kollidon CL-SF, Kollicoat SR 30D||BASF||Good flow, creamier mouthfeel, disintegration functionality, tablet hardness with low friability, tailor-made for ODTs|
|Ludipress||Lactose, Kollidon 30, Kollidon CL||BASF||Low hygroscopicity, good flowability, disintegrant functionality|
|MicroceLac||MCC, Lactose||Meggle||Excellent compressibility for high dose formulations, good flow|
|PanExcea MCC333G||MCC, HPMC, Crospovidone||Mallinckrodt Baker||Good flow and high compressibility, High API loading, composite particle with binder, filler and disintegrant functionality|
|Pharmatose DCL 40||Beta-Lactose, Lactitol||DMV Veghel||Good flowability, high dilution potential, low water uptake at high humidity|
|Prosolv||MCC, Colloidal silicon dioxide||Penwest||Good flow, reduced sensitivity to wet granulation, hard tablets with low friability|
|StarCap 1500||Corn starch, Pregelatinized starch||Colorcon||Low-dust excipient with disintegration properties and dissolution behavior that are independent of the media pH|
|Star Lac||Lactose, Maize starch||Roquette||Good flow with disintegration functionality; ideal for ODTs|
|Xylitab 100||Xylitol, Polydextrose||Danisco sugars||Directly compressible sugar with improved mouthfeel|
Enhanced compressibility: Co-processed excipients show remarkable improvement in the compressibility of the material. It is observed that the co-processed products have better compressibility as compared to the physical mixtures of the same components. The co-processed excipient also gives us the advantage of retaining the compactibility when diluted with another material (termed as dilution potential). Thus, co-processed excipients are an ideal choice for developing DC formulation of API with poor compressibility. In fact, some excipients (such as Pharmatose DCL 40) are so developed that they can incorporate a large amount of drug without losing compactibility and hence are well-suited for high dose formulations.
Easy scale-up: Improved flow and good compactability coupled with multiple functions helps in developing formulas with a minimum of ingredients. Thus, such formulations show better adaptability to scale-up (especially on high-speed machinery) with minimum variation. The reduction in the number of ingredients in the inventory is also a welcomed change for industry, as it reduces the cost and time incurred during purchase and release of materials. In addition, it is a big relief for analysts, who can save time and the hassle of analyzing multiple excipients as per the specifications.
Special applicability in ODT formats: Single-bodied multifunctional excipients like Ludiflash, F-MELT, Avicel CE-15 are especially developed for ODT formulations. They are tailor-made in order to give binding during compression (to produce a hard tablet at a minimum compression pressure) and show rapid disintegration when brought in contact with a medium. They are processed in such a way that they give a creamier mouthfeel on disintegration, thereby improving the overall palatability of the formulation. In some cases (like Ludiflash, which composes of around 90% mannitol) the excipient itself imparts a sweet taste to the product, cutting down on the need for sweetener in the formulation.
Other advantages associated with the use of multifunctionality excipients include reduced dust generation, easy flow of normal processing steps, reduced lubricant sensitivity, suitability of excipient for wet granulation, dry granulation and direct compression, robust tabletting at low compression pressure and IP benefits in terms of propriety combinations.
Multifunctional excipients are used to serve a wide array of purposes. Many of these excipients have already made a mark in the market and they have found their mentions in Handbook of Pharmaceutical Excipients (the most common source of information for formulators). Above is a list of multifunctional excipients available commercially.
Introduction of these multifunctional excipients has really helped in solving formulation development issues. Use of single-bodied excipients has made life easy for formulators as the optimization efforts have decreased considerably. Also, the scaleup suitability of these excipients results in development of robust formulations that show fewer problems during technology transfer. Moreover, these excipients also serve the role of novel excipients and their potentials can be explored and exploited in different possible ways. Thanks to these excipients, formulators now have number of alternatives to explore.