You are on page 1of 4

Technology & Services

PROSOLV
a report by

High Functionality Excipients (HFE) SMCC as an Effective Strategy for Generic Drug Formulation

J o s e p h A Z e l e z n i k and J e n n i f e r R e n a k
Research Manager and Scientist, JRS Pharma LP

As the generic pharmaceutical industry competitive climate becomes more complex, formulation scientists are faced with an ever-increasing challenge to develop solid dosage formulations quickly and economically. First-to-file opportunities are critical for capturing market share. Formulation development economics have gone beyond simply using inexpensive raw materials and now not only require development cost assessments, but also scaleup and manufacturing costs. Simplified formulations and processes provide the most effective route to accomplishing such goals, while conventional formulation ingredients and approaches may limit opportunities. With the introduction of high functionality excipients (HFE), formulation scientists in the generic pharmaceutical industry have access to unique materials in providing simplified formulations both in terms of ingredients and processes while maintaining overall economic value. Developing direct compression formulations generally requires several conventional excipients. Good formulation flow, compaction, powder blending, content uniformity and carrying capacity, enhanced stability, lubricity and dosage form disintegration all rely on formulation scientists choosing ingredients that best provide those attributes necessary for successful formulations. Identifying excipient combinations in optimum concentrations to achieve adequate solid dosage forms often requires significant time and expensive processes, which vary with active pharmaceutical ingredient (API) characteristics. Excipient technology advancements have led to a new class of HFE, which simplify formulation. HFE are inactive ingredients that meet four unique criteria. Firstly, they are multifunctional. They do not perform a single function, like glidants, lubricants, anti-adherents, binders or disintegrants. HFE combine two or more functions through a single ingredient. Secondly, HFE have high inherent functional performance allowing for increased batch sizes and higher drug-loading, even at low usage

levels. Thirdly, HFE require no complex processing, making them ideal for direct compression processes. Lastly, HFE impart their high inherent performance characteristics to the overall formulation. This last criterion is critical and separates HFE from other multi-functional excipients or conventional speciality excipients. HFE provide several functions to a drug formulation (such as high intrinsic flow, compactability and disintegration attributes), using fewer ingredients, simplifying final dosage forms and the manufacturing process. HFE provide formulators with the means to achieve finished dosage forms with minimal inert ingredients (both in number and level). In many instances achieving desired formulation functionality requires complex processing, such as wet granulation techniques, to establish uniform, robust formulations. Traditional approaches often require high ingredient use to achieve acceptable API loading, since conventional excipients do not impart functional performance to the overall formulation. Special grades of conventional excipients generally offer one primary function, often at the expense of several others. They do not impart their inherent functionality any more than the parent material. Costly processing might be required to achieve an effective functional formulation. Examples include microcrystalline cellulose, where density and/or particle size have been altered to improve flow or compaction. Yet, when one attribute has been enhanced, the other is compromised. That is, flow is improved at the expense of compaction and vice versa. Another example, co-processed cellulose and lactose, is no more than a special lactose grade with improved compaction properties. Dr Arvind K Bansal correlate formulation with modifications functionality.1 What he is, in many instances, pre-existing excipient et al., were the first to performance differences in inherent excipient termed high functionality merely a special grade of that generates improved

1. Bansal A K and Nachaegari S K, High-Functionality Excipients for Solid Dosage Forms, Business Briefing: PharmaGenerics (September 2002), p. 38.
BUSINESS BRIEFING: PHARMAGENERICS 2004

Technology & Services

Figure 1: PROSOLV SMCC Silicified Microcrystalline Cellulose.

PROSOLV SMCC Silicified Microcrystalline Cellulose at 10,000x magnification demonstrates the increased surface roughness that results from uniformly and completely dispersing colloidal silicon dioxide across microcrystalline cellulose during co-processing.

increased functional performance and imparting high multi-functionality to API formulations. The CSD is uniformly and highly dispersed across the cellulose surface (see Figure 1), which provides a five-fold surface area increase compared with traditional MCC (see Figure 2). Previous findings document this coprocessed material as demonstrating enhanced multifunctionality regarding compactibility, flow, blending properties, lubricant insensitivity and tablet disintegration. The enhanced functional performance is imparted to direct compression formulations and formulators have taken notice. Since its introduction, PROSOLV SMCC has been applied to numerous pharmaceutical formulations and has gained worldwide acceptance and approval. PROSOLV SMCCs applications have been diverse and many. There have been many examples where the technology has provided formulation scientists with the means to simplify formulations by replacing several traditional excipients with one, eliminating costly and complex processes. PROSOLV SMCC not only replaces many of the traditional excipients used in formulation development, but does so at lower usage levels. Traditional excipients used in combination still do not perform as well as PROSOLV SMCC, due to the synergistic performance enhancement, and require increased levels to match PROSOLV SMCCs performance (see Figure 3). PROSOLV SMCC has demonstrated an ability to disperse low-dose APIs uniformly in direct compression tablet formulations, without costly and complex granulation techniques. Four pharmaceutical manufacturers Lundbeck5, Pfizer6, Novo Nordisk7 and Mova8 have demonstrated enhanced API content uniformity using PROSOLV SMCC in their API formulations. This is particularly notable since it was achieved through direct compression processing. PROSOLV SMCCs increased surface area, and high degree of surface roughness compared with traditional microcrystalline cellulose, generated increased powder shear in dry blending, which enhanced API dispersion and allowed the low-dose API to become stabilised uniformly throughout the powder bed. API stability enhancement in formulations has also been demonstrated with PROSOLV SMCC. Pfizer demonstrated decreased ferrous ion

Figure 2: Microcrystalline Cellulose at 10,000x Magnification

The cellulose surface is smooth and has a much lower surface area than SMCC.

functional performance for one functional characteristic, without improving overall material or formulation functionality. HFE have secured credibility in recent years by effectively enhancing and simplifying pharmaceutical and nutritional formulations.2,3 PROSOLV SMCC is one multi-functional excipient example meeting HFE definition criteria. Introduced in 1996 as a patented technology platform, PROSOLV SMCC silicified microcrystalline cellulose combines 98% microcrystalline cellulose (MCC) and 2% fumed colloidal silicon dioxide (CSD) in a patented coprocessed intimate mixture.4 Although co-processed, the two excipients maintain their independent chemical properties while synergistically providing

2. BioInnovators, Inc., Press Release, BioInnovators Develops Excipio Economics (11April 2003). 3. Tableting Binder Improves Production, Nutritional Outlook, Tech File (March 2001). 4. Sherwood B E and Becker J W, A New Class of High Functionality Excipients: Silicified Microcrystalline Cellulose, Pharmaceutical Technology (October 1998). 5. Liljegren K, et al., Patent Application 20030109577, assigned to Lundbeck H A/S (5 December 2000). 6. Gierer D S, Patent Application 20030004182, assigned to Pfizer Inc. (23 April 2002). 7. Hjorth T B, et al., Patent Application 20030050312, assigned to Novo Nordisk (12 March 12 2002). 8. Frontanes R A, et al., International Patent Publication WO 01/7444/A1, assigned to Mova Pharmaceutical, Inc.

BUSINESS BRIEFING: PHARMAGENERICS 2004

High Functionality Excipients


oxidative degradation when combined with SMCC compared with conventional excipients.9 Mova demonstrated a 50% reduction in levothyroxine degradation in a direct compression formulation using PROSOLV SMCC.10 Since levothyroxine is known to degrade in the presence of lactose, formulating with PROSOLV SMCC eliminated the lactose requirement, allowing for increased API stability. Higher drug-loading has been achieved using PROSOLV SMCC. It has also exhibited the ability to absorb oily, tacky or cohesive drug actives and retain high compactability. Ross Laboratories demonstrated this effect for divalproex sodium formulations.11 Cima Laboratories12 and Johnson & Johnson13 utilised an oil carrier substance and then achieved compactability using PROSOLV SMCC as their direct compression binder. Since CSD not only resides on PROSOLV SMCCs surface, but internally as well, PROSOLV SMCC possesses a brittle fracture component. This allows for new bonding surfaces to be formed during compaction, despite the presence of oily active coating particles within the formulation matrix, allowing for improved compactability. Cima Laboratories formulations were for a lovostatin emulsion formulation complexed with CSD as the carrier. Johnson & Johnsons formulations were for simethicone using magnesium alumino silicate as the carrier and high-density silicified microcrystalline cellulose, PROSOLV HD 90, as the direct compression binder. Antibiotic formulations are also particularly sensitive to formulation ingredient choices and processing. Rudnic, et al., demonstrated effectiveness for PROSOLV SMCC in clarithromycin extrusion, spheronisation and tableting.14 Professor Newton at The University of London has conducted extensive extrusion and spheronisation studies demonstrating the performance enhancement of PROSOLV SMCC with drugs of low, medium and high aqueous solubility.15 PROSOLV SMCC is an accepted ingredient by the US Food and Drug Administration (FDA) and is listed on the FDAs website in the Inactive
Figure 3: Traditional Formulation Approaches Require More Excipients at Increased levels. PROSOLV SMCC Formulations are Simplified in Terms of Ingredient Numbers and Levels and Processing

Ingredients Guide (IIG). It has also been used and accepted in several European applications and is now accepted for use in Japan. A drug master file (DMF) has been created and filed with the FDA. Because PROSOLV SMCC is an HFE and provides significant functional performance, it may offer formulators a means to develop unique dosage forms for the branded generic market segment, providing substantial economic benefits with regard to revenue streams. PROSOLV SMCC also offers other economic benefits internally, beyond ingredient costs. Formulation development time and the time required for scaling formulations from bench to manufacturing can be greatly reduced. As a direct result, API consumption is decreased; formulations are finalised sooner, which provides first-to-file opportunities; excipient-release testing is decreased due to fewer ingredients; in-process testing is eliminated for complex processing, since direct compression formulations become not only possible, but preferred; throughput increases; and manufacturing yields increase. PROSOLV SMCC may also offer another unique advantage for the generic pharmaceutical industry: since it is an HFE, it might be possible that

9. Wang H, Patent Application 20010047034, assigned to Pfizer, Inc. (9 March 2001). 10. Frontanes R A, et al., International Patent Publication WO 01/7444/A1, assigned to Mova Pharmaceutical, Inc. 11. Qui Y, et al., Patent Application 20020132010, assigned to Ross Laboratories Division Of Abbott Laboratories (22 December 22 2000). 12. Pather S I, et al., Patent Application 20020160049, assigned to Cima Labs, Inc. (23 February 23 2001). 13. Szymczak C E, et al., Patent Application 20030091624, assigned to Johnson & Johnson, (28 September 2003). 14. Rudnic E M, et al., Patent Application 20010048944, assigned to Advances Pharmaceutical Corporation (22 February 2001). 15. Newton J M, The Preparation of Pellets with Silicified Microcrystalline Cellulose by Extrusion and Spheronization EUFEBS Conference (June 2002).

BUSINESS BRIEFING: PHARMAGENERICS 2004

Technology & Services

non-infringing formulations could be developed due to the simplistic formulation approach the product offers. This is particularly important in a market segment where competition continues to increase and the number of innovator patents increases and becomes more complex. This is not to say that PROSOLV SMCC can be used in all instances to overcome patent obstacles; rather, the opportunity may exist for some barriers to be removed. HFE are a reality and have gained wide

acceptance across multiple industries and industry segments. They are particularly important to the generic pharmaceutical industry, since development and production can be streamlined, saving time and money. A competitive advantage can be realised, which will advance market share and increase revenue. PROSOLV SMCC is one such HFE. It can ease the formulation scientists burden by decreasing many of the challenges formulators face today. The number of successes PROSOLV SMCC offers is limited only by the formulators imagination.

BUSINESS BRIEFING: PHARMAGENERICS 2004

You might also like