High Bulk-Density Amorphous Dispersions to Enable Direct Compression of Reduced Tablet Size Amorphous Dosage Units.

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets.

Densifying Co-Precipitated Amorphous Dispersions to Achieve Improved Bulk Powder Properties.

PURPOSE: Precipitation of amorphous solid dispersions has gained traction in the pharmaceutical industry given its application to pharmaceuticals with varying physicochemical properties. Although preparing co-precipitated amorphous dispersions (cPAD) in high-shear rotor-stator devices allows for controlled shear conditions during precipitation, such aggressive mixing environments can result in materials with low bulk density and poor flowability. This work investigated annealing cPAD after precipitation by washing with heated anti-solvent to improve bulk powder properties required for downstream drug product processing. METHODS: Co-precipitation dispersions were prepared by precipitation into pH-modified aqueous anti-solvent. Amorphous dispersions were washed with heated anti-solvent and assessed for bulk density, flowability, and dissolution behavior relative to both cPAD produced without a heated wash and spray dried intermediate. RESULTS: Washing cPAD with a heated anti-solvent resulted in an improvement in flowability and increased bulk density. The mechanism of densification was ascribed to annealing over the wetted Tg of the material, which lead to collapse of the porous co-precipitate structure into densified granules without causing crystallization. In contrast, an alternative approach to increase bulk density by precipitating the ASD using low shear conditions showed evidence of crystallinity. The dissolution rate of the densified cPAD granules was lower than that of the low-bulk density dispersions, although both samples reached concentrations equivalent to that of the spray dried intermediate after 90 min dissolution. CONCLUSIONS: Hot wash densification was a tenable route to produce co-precipitated amorphous dispersions with improved properties for downstream processing compared to non-densified powders.

Flexibility in Drug Product Development: A Perspective.

The process of bringing a drug to market involves innumerable decisions to refine a concept into a final product. The final product goes through extensive research and development to meet the target product profile and to obtain a product that is manufacturable at scale. Historically, this process often feels inflexible and linear, as ideas and development paths are eliminated early on to allow focus on the workstream with the highest probability of success. Carrying multiple options early in development is both time-consuming and resource-intensive. Similarly, changing development pathways after significant investment carries a high "penalty of change" (PoC), which makes pivoting to a new concept late in development inhibitory. Can drug product (DP) development be made more flexible? The authors believe that combining a nonlinear DP development approach, leveraging state-of-the art data sciences, and using emerging process and measurement technologies will offer enhanced flexibility and should become the new normal. Through the use of iterative DP evaluation, "smart" clinical studies, artificial intelligence, novel characterization techniques, automation, and data collection/modeling/interpretation, it should be possible to significantly reduce the PoC during development. In this Perspective, a review of ideas/techniques along with supporting technologies that can be applied at each stage of DP development is shared. It is further discussed how these contribute to an improved and flexible DP development through the acceleration of the iterative build-measure-learn cycle in laboratories and clinical trials.

Drug solubility in fatty acids as a formulation design approach for lipid-based formulations: a technical note.

Lipid-based drug delivery systems have been intensively investigated as a means of delivering poorly water-soluble drugs. Upon ingestion, the lipases in the gastrointestinal tract digest lipid ingredients, mainly triglycerides, within the formulation into monoglycerides and fatty acids. While numerous studies have addressed the solubility of drugs in triglycerides, comparatively few publications have addressed the solubility of drugs in fatty acids, which are the end product of digestion and responsible for the solubility of drug within mixed micelles. The objective of this investigation was to explore the solubility of a poorly water-soluble drug in fatty acids and raise the awareness of the importance of drug solubility in fatty acids. The model API (active pharmaceutical ingredient), a weak acid, is considered a BCS II compound with an aqueous solubility of 0.02 µg/mL and predicted partition coefficient >7. The solubility of API ranged from 120 mg/mL to over 1 g/mL in fatty acids with chain lengths across the range C18 to C6. Hydrogen bonding was found to be the main driver of the solubilization of API in fatty acids. The solubility of API was significantly reduced by water uptake in caprylic acid but not in oleic acid. This report demonstrates that solubility data generated in fatty acids can provide an indication of the solubility of the drug after lipid digestion. This report also highlights the importance of measuring the solubility of drugs in fatty acids in the course of lipid formulation development.

Producing Amorphous Solid Dispersions via Co-Precipitation and Spray Drying: Impact to Physicochemical and Biopharmaceutical Properties.

Many small-molecule active pharmaceutical ingredients (APIs) exhibit low aqueous solubility and benefit from generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot-melt extrusion are 2 common methods to produce these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route. Herein, amorphous solid dispersions of compound A, a low-solubility weak acid, and copovidone were made by conventional spray drying and co-precipitation. The physicochemical properties of the 2 materials were assessed via X-ray diffraction, differential scanning calorimetry, thermal gravimetric analysis, and scanning electron microscopy. The amorphous dispersions were then formulated and tableted, and the performance was assessed in vivo and in vitro. In human dissolution studies, the co-precipitation tablets had slightly slower dissolution than the spray-dried dispersion, but both reached full release of compound A. In canine in vitro dissolution studies, the tablets showed comparable dissolution profiles. Finally, canine pharmacokinetic studies showed that the materials had comparable values for the area under the curve, bioavailability, and Cmax. Based on the summarized data, we conclude that for some APIs, co-precipitation is a viable alternative to spray drying to make solid amorphous dispersions while maintaining desirable physicochemical and biopharmaceutical characteristics.

Detection of a minor amorphous phase in crystalline etoricoxib by dynamic mechanical analysis: comparison with Raman spectroscopy and modulated differential scanning calorimetry.

Detection and quantification of the amorphous phase of etoricoxib bulk drug substances, a selective cycloogenase-2 inhibitor used for the treatment of osteoarthritis, rheumatoid arthritis, and dental pain, was carried out using modulated differential scanning calorimetry (MDSC), dynamic mechanical analysis (DMA), and Raman spectroscopy. Detection of amorphous content in pharmaceutical powders by DMA is a special application of dynamic mechanical spectroscopy. DMA was found to be a sensitive technique, able to detect the presence of an amorphous phase in a crystalline phase at concentrations as low as 0.5%. The limit of detection (LOD) determined for DMA was 2.5%. In comparison, Raman spectroscopy and MDSC had LOD values of 2% and 5% amorphous, respectively.

Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases.

In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.

Physicochemical characterization of five glyburide powders: a BCS based approach to predict oral absorption.

The purpose of this study was to investigate the suitability of physicochemical parameters of Active Pharmaceutical Ingredients (APIs) as input functions for the Advanced Compartmental Absorption and Transit Model (ACAT) to predict the oral absorption of drug products. Five different glyburide APIs were characterized using X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Raman spectroscopy, particle size and particle size distribution, specific surface area and true density measurements, as well as dissociation constant (pKa), partition coefficient (log P) and distribution coefficient (log D). The computer simulations were performed using GastroPlus. The results of XPRD, DSC and Raman spectroscopy indicated that no significant differences in crystal form were present in the five APIs. However, significant differences in particle size and particle size distribution were observed. A basic in vitro/in vivo relationship between the APIs' particle size and clinically observed plasma time profiles was established. The study demonstrates that in silico methods can assist the formulation scientist to set meaningful API specifications. Computer simulations could shorten the drug development process since appropriate bioawaivers, based on data from simulation studies, may be justified.

Investigating the hydrate conversion propensity of different etoricoxib lots.

The physical stability of bulk active pharmaceutical ingredients (API) is of significant scientific and regulatory concern. Carrying out physical stability testing on lots with varying rates of hydrate conversion can potentially lead to erroneous conclusions if these rate differences remain unknown and unstudied. The lot dependency of etoricoxib's rate of hemihydrate conversion was investigated and a quick discriminatory technique was developed to qualitatively assess relatively slow to rapidly converting lots. This novel technique was also used to screen potential parameters affecting the hydrate conversion rate such as particle size/surface area, amorphous content, and initial hemihydrate content. Based on qualitative X-ray powder diffraction (XRPD) and quantitative Raman data, significant effects on the rate of hydration were observed with the addition of small amounts of amorphous etoricoxib. Furthermore, it was found that the presence of hemihydrate also increased the rate of conversion by seeding anhydrous etoricoxib. This suggests that the initial presence of the hydrate form can cooperatively accelerate conversion. A better understanding of the factors affecting hydrate conversion rates resulted in the appropriate selection of storage conditions for both the bulk API and the formulated product.