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Excipients for lowering formulation costs and improving lipid-based formulations and the use of melt-spray-congeal microsphere sachet technology for targeted controlled release attract attention at the 2013 American Association of Pharmaceutical Scientists Annual Meeting.
The American Association of Pharmaceutical Scientists (AAPS) provides a dynamic international forum for the exchange of knowledge between members employed in industry, academia, government, and other research institutes worldwide. Many of these members converged on San Antonio, Texas the week of November 10 for the AAPS Annual Meeting and Expo to present and discuss the discovery, design, analysis, development, production, quality control, safety, clinical evaluation, regulation, distribution, and utilization of drugs and drug delivery systems. Several new products/technologies for the formulation of solid dosage drugs were introduced and/or reviewed at the meeting. Some highlights are presented below.
Roller compaction and direct compression for matrix tablet applications
To meet the expectations of its pharmaceutical manufacturing customers to save time and money in tablet manufacture while maintaining reproducibility, uniformity, and consistent modified release performance, the Dow-Colorcon Controlled Release Alliance (CR Alliance) has developed METHOCEL DC2. This polymeric hydroxypropyl methylcellulose (HPMC) excipient, the next-generation offering beyond METHOCEL CR, has a specially designed morphology that enables a noticeable improvement in the flow properties of powder blends, facilitating roller compaction and direct compression of matrix tablets, according to True Rogers, technologies leader for Dow Pharma & Food Solutions.
Using METHOCEL DC2 can enable tablet manufacturers to switch from wet granulation to direct compression or roller compaction, both of which are dry production techniques that require fewer processing steps. As a result, manufacturing costs can be reduced by as much as 60% and both waste and development times can be reduced, according to Rogers. “Direct compression methods also offer better formulation options for heat- and moisture-sensitive APIs. In addition, tablets formulated with METHOCEL DC2 exhibit both higher reproducibility in terms of weight and hardness and more accurate and precise API content uniformity from tablet-to-tablet,” he notes. Process control is higher during tablet manufacture, and confidence intervals on tablet properties can be tightened down accordingly.
Importantly for solid-dosage drug manufacturers, METHOCEL DC2 is chemically identical to METHOCEL CR and thus meets all HPMC pharmacopeial requirements. In addition, the CR Alliance has demonstrated the benefits of the new METHOCEL DC2 excipient in a number of model API formulations.
Three direct compression grades are currently available: METHOCEL K100LV Premium DC2, METHOCEL K4M Premium DC2, and METHOCEL K100M Premium DC2. These polymers have been developed to optimize dry powder processability while maintaining the same viscosities, degrees of methoxyl and hydroxypropyl substitution, and other important properties as the Controlled Release (CR) grade equivalents. These cGMP materials are currently being supplied from a Dow market development plant, and a full-scale manufacturing facility is on schedule to begin production in the second half of 2014.
Silica carrier for lipid-based drug delivery systems
Lipid-based formulations pose a number of formulating challenges, such as difficult handling and stability limitations, capsule compatibility, shelf-life issues, and less-than-ideal filling efficiencies, particularly in solid dosage forms, according to Bill McCarthy from Grace Materials Technologies. To address these issues, the company has engineered an optimized mesoporous, amorphous, silica gel excipient with a unique morphology for the transformation of liquids, and particularly oil actives and lipid-based systems, into free flowing solids. SYLOID XDP provides a balance of absorption capacity, density, and release that can increase API loading and desorption in solid dosage forms, including capsules, tablets, and self-emulsifying drug delivery systems (SEDDS).
Lipids are increasingly being used in formulations today as drug solubilizers, adsorption enhancers, and vehicles for lipid-based drug delivery in order to increase the oral bioavailability of poorly soluble drugs. “It is a challenge, however, to convert oily solutions and liquid formulations into compressible, solid or semi-solid formulations. The unique combination of adsorption capacity, porosity, particle size, and density of SYLOID XDP provides a tool for creating free-flowing powder formulations that can expedite manufacturing and improve the efficacy of the final dosage form for lipids, oily drugs, and drugs in oil solutions,” observes McCarthy.
In volume-constrained systems such as capsules and tablets, carriers must be able to deliver the largest amount of liquid per volume. The combined internal and external porosity of Syloid XDP silicas allows a greater surface area and a higher adsorptive capacity, or optimum loadabiltiy for oils, lipids and liquids that are commonly used for solubilizing and loading APIs, according to McCarthy.
Importantly, because of the unique morphology of Syloid XDP silica, lipid systems can be directly loaded without the need to use a solvent or drying, which simplifies the liquid to solid transformation. Studies at Grace have shown that in a standard capsule, the new silica excipient not only enabled a significantly higher loading, it provided the most complete release of loaded oils (sesame oil, Miglyol 812, and tocopherol) compared to that observed for granulated fumed silica and magnesium aluminum silicate.
Melt-spray-congeal microsphere platform technology for controlled delivery
Developing an appropriate controlled release technology can be a challenge when the API involved has a narrow target window for performance. Dan Dobry, vice-president of Bend Research, a part of Capsugel’s Dosage Form Solutions business, addressed this issue in a presentation on Bend Research’s collaboration with Pfizer to develop a controlled-release technology for Zmax, a single-dose version of the antibiotic azithromycin, which is now approved in the United States for community-acquired pneumonia and acute bacterial sinusitis.
The controlled-release technology had to meet a narrow target window between poor tolerability and poor absorption (in the colon) using a high, single oral dose of 2 g. Given the high dose, a sachet product was needed. After evaluation of various options, the collaborators elected to use a melt-spray-congeal microsphere technology; the produced sachet would provide the desired controlled release and also offer very good mouth feel due to the size and shape of the microspheres, according to Dobry.
To prepare the microspheres, a crystalline suspension of the API is dispersed in a waxy melt, which is then atomized using a spinning disk in a designed fashion to control the size of the generated microspheres (~ 200 µm), followed by congealing of the microspheres by contact with cool air. The waxy matrix consists of an insoluble carrier and a soluble pore former (dissolution enhancer). For this particular formulation, the drug is released via aqueous pore diffusion when the microspheres are exposed to the aqueous, alkaline environment in the stomach and the dissolution enhancer is dissolved. “Understanding the release mechanism is key to developing controlled release microspheres,” Dobry explains. “In this case, the dissolution rate increases approximately linearly with increasing temperature, which indicates that drug diffusion occurs through open porous channels that are large compared to the dimensions of the drug.”
While melt-spray-congeal processing was not new prior to this project, it was applied in a novel way for production of these microspheres. Bend Research is currently exploring the application of the microsphere technology for the modified controlled-release of other drug substances. “We believe this technology is a platform technology that can be used for a number of applications (particularly pediatric/geriatric formulations), such as sustained release, immediate release or bioenhancement, the improvement of chemical stability or protection from excipients, and taste masking with or without a coating,” says Dobry. He adds that the process is appropriate for drugs with a wide range of physicochemical properties as long as their melt point is greater than 100–120 °C. The generated microspheres can be readily coated with thin films for applications such as tastemasking. The good mouth feel of the microspheres is due to the unique combination of small size, spherical shape, and the waxy materials used.
From particles to capsules to taste masking
Several other companies highlighted different advanced solutions for solid dosage formulations. Patheon, for example, presented on topics including particle engineering, material properties and techniques for solubility enhancement, roller compaction and tableting, taste masking, multiparticulates, softgels, and fixed dose combinations. BASF, meanwhile, used a platform solution concept including technologies designed to improve the efficacy, bioavailability, and compliance of pharmaceutical products. The five market platforms that the company emphasized included modified release, solubilization, softgels, skin delivery, and taste masking.