Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on the physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility and miscibility. However, structural details for understanding the nature of the molecular contacts and mechanistic roles in various physicochemical and thermodynamic events often remain unclear. This study provides a spectroscopic characterization of posaconazole (POSA) formulations, a second-generation triazole antifungal drug (Noxafil, Merck & Co., Inc., Kenilworth, NJ, USA), at molecular resolution. One- and two-dimensional (2D) solid-state NMR (ssNMR) techniques including spectral editing, heteronuclear 1H–13C, 19F–13C, 15N–13C, and 19F–1H polarization transfer, and spin correlation and ultrafast magic angle spinning, together with the isotopic labeling strategy, were utilized to uncover molecular details in POSA ASDs in a site-specific manner. Active groups in triazole and difluorophenyl rings exhibited rich but distinct categories of interactions with two polymers, hypromellose acetate succinate and hypromellose phthalate, including intermolecular O–H···OC and O–H···F–C hydrogen bonding, π–π aromatic packing, and electrostatic interaction. Interestingly, the chlorine-to-fluorine substituent in POSA, one of the major structural differences from itraconazole that could facilitate binding to the biological target, offers an additional contact with the polymer. These findings exhibit 2D ssNMR as a sensitive technique for probing sub-nanometer structures of pharmaceutical materials and provide a structural basis for optimizing the type and strength of drug–polymer interactions in the design of amorphous formulations.

Rotor−stator wet mills are commonly used in the pharmaceutical industry to reduce particle size and normalize API physical properties as a means to facilitate downstream drug product operations and/or achieve targeted in vivo product performance. Wet milling is robust, relatively easy to use, broadly applicable, and offers both financial and API physical property advantages over dry milling. Historical rotor−stator wet mill technologies are generally capable of achieving particles sizes down to ∼25 μm. Newer high-shear wet mills allow for a reduction of particle size down to ∼10−15 μm. In addition to the improved particle size reduction, recent wet mill designs better maintain geometric consistency across the product line, thereby providing enhanced scalability. A traditional scale-up approach for wet milling involved maintaining the tip speed of the rotor (assuming constant shear gap and thus constant shear rate) and would generally allow comparable terminal particle size (that near steadystate particle size where particle size reduction drastically slows) across scales. In order to predict the milling time upon scale-up the number of passes, or batch turnover, through the mill was kept constant. However, this prediction of the required milling time was often less successful than the prediction of the terminal particle size. Studies presented here confirmed the importance of maintaining constant rotor tip speed across scales to achieve the predicted terminal particle size and identified the importance of additional parameters to address particle breakage kinetics to allow prediction of the required milling time to achieve the target particle size. Additional aspects of hydrodynamics, shear rates, and equipment properties were assessed as part of these scale-up model optimization efforts. Specific processing parameters evaluated included flow rate, API slurry solids concentration, and starting particle size distribution. Ultimately, the Slot Event Model was developed to incorporate the critical geometric parameters by considering the frequency and the probability of a slot event. In addition to applying the revised model across scales, further model verification was achieved by evaluating custom rotor−stator mill heads. Studies with these custom mill heads provided insight into the importance of mill efficiency and slot events. This, in turn, allowed for more accurate scale-up of not only the terminal particle size but also the milling time required to achieve the target particle size. The success of the optimized model reduces the reliance on in-process controls or at-line testing for determining the end point of milling.

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.

Amorphous solid dispersions (ASDs) are a well-documented formulation approach to improve the rate and extent of dissolution for hydrophobic pharmaceuticals. However, weakly basic compounds can complicate standard approaches to ASDs due to pH-dependent solubility, resulting in uncontrolled drug release in gastric conditions and unstabilized supersaturated solutions prone to precipitation at neutral pH. This work examines the release mechanisms of amorphous dispersions containing model weakly basic pharmaceuticals posaconazole and lumefantrine from a basic poly­(dimethylaminoethyl methacrylate) copolymer (Eudragit EPO) and compares their dissolution behavior with ASDs stabilized by acidic and neutral polymers to understand potential benefits to release from a basic polymeric stabilizer. It was found that dissolution of Eudragit EPO ASDs resulted in supersaturation under gastric conditions, which could be sustained upon adjustment to neutral pH. However, the dissolution behavior of Eudragit EPO ASDs was sensitive to the initial pH of the gastric media. For lumefantrine, elevated initial gastric pH resulted in precipitation of amorphous nanoparticles; for posaconazole, elevated gastric pH led to crystallization of the pharmaceutical from solution. This sensitivity to gastric pH was found to originate from the impact of Eudragit EPO on gastric pH and the solubility of each pharmaceutical in the first stage of dissolution. In total, these data illustrate benefits and liabilities for the use of Eudragit EPO for ASDs containing weak pharmaceutical bases to guide the design of robust pharmaceutical formulations.

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 C. 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.

No abstract

No abstract

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.