Optimized physical properties (e.g., bulk, surface/interfacial, and mechanical properties) of active pharmaceutical ingredients (APIs) are key to the successful integration of drug substance and drug product manufacturing, robust drug product manufacturing operations, and ultimately to attaining consistent drug product critical quality attributes. However, an appreciable number of APIs have physical properties that cannot be managed via routes such as form selection, adjustments to the crystallization process parameters, or milling. Approaches to control physical properties in innovative ways offer the possibility of providing additional and unique opportunities to control API physical properties for both batch and continuous drug product manufacturing, ultimately resulting in simplified and more robust pharmaceutical manufacturing processes. Specifically, diverse opportunities to significantly enhance API physical properties are created if allowances are made for generating co-processed APIs by introducing nonactive components (e.g., excipients, additives, carriers) during drug substance manufacturing. The addition of a nonactive coformer during drug substance manufacturing is currently an accepted approach for cocrystals, and it would be beneficial if a similar allowance could be made for other nonactive components with the ability to modify the physical properties of the API. In many cases, co-processed APIs could enable continuous direct compression for small molecules, and longer term, this approach could be leveraged to simplify continuous end-to-end drug substance to drug product manufacturing processes for both small and large molecules. As with any novel technology, the regulatory expectations for co-processed APIs are not yet clearly defined, and this creates challenges for commercial implementation of these technologies by the pharmaceutical industry. The intent of this paper is to highlight the opportunities and growing interest in realizing the benefits of co-processed APIs, exemplified by a body of academic research and industrial examples. This work will highlight reasons why co-processed APIs would best be considered as drug substances from a regulatory perspective and emphasize the areas where regulatory strategies need to be established to allow for commercialization of innovative approaches in this area.

Recent Advances in Co-processed APIs and Proposals for Enabling Commercialization of These Transformative Technologies.

Recent advances in life science technology have prompted the need to develop microcapsule delivery systems that can encapsulate many different functional or active materials such as drugs, peptides, and live cells, etc. The encapsulation technology is now commonly used in medicine, agriculture, food, and other many fields. The application of biodegradable microcapsule systems can not only effectively prevent the degradation of core materials in the body or the biological environment, but also improve the bioavailability, control the release and prolong the halftime or storage of core active materials. Various wall materials, preparation methods, encapsulation processes, and release mechanisms are covered in this review, as well as several main factors including pH values, temperatures, particle sizes, and additives, which can strongly influence the encapsulation efficiency, the strength, and release of microcapsules. The improvement of coating materials, preparation techniques, and challenges are also highlighted, as well as application prospects.

Recent progress in preparation and agricultural application of microcapsules

Dosage form designs for the controlled drug release of solid dispersions.

Co-precipitation is an emerging method to generate amorphous solid dispersions (ASDs), notable for its ability to enable the production of ASDs containing pharmaceuticals with thermal instability and limited solubility. As is true for spray drying and other unit operations to generate amorphous materials, changes in processing conditions during co-precipitation, such as solvent selection, can have a significant impact on the molecular and bulk powder properties of co-precipitated amorphous dispersions (cPAD). Using posaconazole as a model API, this work investigates how solvent selection can be leveraged to mitigate crystallization and maximize bulk density for precipitated amorphous dispersions. A precipitation process is developed to generate high-bulk-density amorphous dispersions. Insights from this system provide a mechanistic rationale to control the solid-state and bulk powder properties of amorphous dispersions.

Optimizing Solvent Selection and Processing Conditions to Generate High Bulk-Density, Co-Precipitated Amorphous Dispersions of Posaconazole

Active pharmaceutical ingredient (API)-based ionic liquids (API-ILs) present an exciting new paradigm for the formulation of poorly water-soluble drugs. In this study, a model room temperature API-IL (1-butyl-3-methyl imidazolium ibuprofenate) was demonstrated to be not just highly soluble but fully miscible and hence have effectively unlimited solubility in water, compared to 0.021 mg mL-1 solubility for the ibuprofen API. Solutions of the API-IL were found to be stable for up to 2 years, indicating that they have the potential to offer thermodynamic stability upon release, avoiding in vivo recrystallization issues that can limit the bioavailability of amorphous solid dispersions (ASDs) and some high-energy crystalline forms. The ibuprofen API-IL was successfully spray-dried into a polymer carrier in loadings of up to 75% w/w in order to transform it into a solid powder suitable for oral solid dosage (OSD) formulation. From modulated differential scanning calorimetry, hot-stage microscopy, powder X-ray diffraction, and attenuated total reflectance Fourier transform infrared spectroscopy measurements, the mechanism by which this high loading was achieved is based on the immiscibility between the polymer and API-IL, with the polymer encapsulating the phase-separated API-IL. Dissolution studies showed that solidification of the API-IL into microcapsules by spray drying in this manner had no detrimental effect on release characteristics. Failure to dissolve crystalline API forms into the polymer matrix eliminates the solubility enhancement of ASDs but not for highly soluble or fully miscible API-ILs. Furthermore, miscible API-IL/polymer dispersions at high loadings were found to possess less-favorable physical properties because of melting point depression, resulting, in some cases, in a failure to form a viable powder. As such, microencapsulated API-ILs at high loadings in immiscible or low-miscibility polymers that have solubility enhancement of the API-IL form, while providing solid powders for processing, represent a promising new platform for the formulation of poorly soluble compounds as OSDs.

Spray Encapsulation as a Formulation Strategy for Drug-Based Room Temperature Ionic Liquids: Exploiting Drug-Polymer Immiscibility to Enable Processing for Solid Dosage Forms.

Building a better particle: Leveraging physicochemical understanding of amorphous solid dispersions and a hierarchical particle approach for improved delivery at high drug loadings.

Jie Ren

Papers

Building a better particle: Leveraging physicochemical understanding of amorphous solid dispersions and a hierarchical particle approach for improved delivery at high drug loadings.