Herein, a population balance model (PBM) for a combined cooling and antisolvent crystallization process for an active pharmaceutical ingredient (API) has been developed and utilized to predict the product particle size distribution (PSD) for two sets of four ∼35 kg scale plant batches, with good agreement to data. The PBM was constructed from lab-scale (∼10 g) crystallization runs using seed and product PSD measurements along with concentration measurements of the API during batch desupersaturation experiments. The PBM was then used to predict the product PSD for two sets of four plant batches, run using different reactors equipped with different agitator types operated at different agitation rates. Analysis of the crystallization kinetics reveals that secondary nucleation due to attrition has a strong influence on the PSD in the crystallization process of the API, and thus mixing conditions (agitator type, agitator speed, pumping, and power numbers) have a strong effect on PSD. The model provides a more robust particle size control strategy than design of experiment (DOE) studies alone by incorporating fundamental crystallization kinetics, with data from a small set of lab experiments in lieu of extensive DOE studies. This firstprinciple-based approach was useful for enhancing the robustness of the technical transfer process by accounting for impacts on product PSD stemming from process scale-up and parameter changes.

Herein we introduce an innovative process for the preparation of a directly compressible active pharmaceutical ingredient (API) and excipient agglomerates for an extended-release formulation of a highly water soluble drug, demonstrated with metformin HCl. Metformin is poorly compressible and currently employs wet granulation for tablet manufacturing, resulting in long cycle times. We have co-processed metformin HCl with hydroxypropyl methylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) in a solvent medium to generate agglomerates that were tableted via direct compression, thereby reducing the drug product manufacturing cycle time and cost while maintaining the extended-release dissolution profile. The intimate mixing of HPMC and NaCMC with metformin HCl through co-processing reduces the risk of segregation during downstream handling and tableting. Additionally, this process reduced the excipient load required to achieve the target dissolution profile and bioequivalence, leading to reduced tablet mass and size with a 1000 mg drug load.

This final communication, of a nine part publication series, details the process development history for the final synthetic step to prepare the drug substance BMS-663068 tris­(hydroxy­methyl)­amino­methane (TRIS) salt. The challenge of developing a robust commercial process to prepare BMS-663068-TRIS salt (active pharmaceutical ingredient, API) was achieved by studying the underlying mechanisms that governed key processing characteristics. Eliminating a slurry-to-slurry transformation results in predictable reaction kinetics and control of impurity formation. Key powder property aspects, such as specific surface area and bulk density, were controlled by examining the impact of seed age, crystallization relative supersaturation (RSS), and particle attrition due to agitation during drying. Ultimately, the processing parameters established for preparation of this drug substance resulted in the generation of the target compound with consistent quality, powder properties, and yield across multiple batches.

A novel process for generating agglomerates of active pharmaceutical ingredient (API) and polymer by swelling the polymer in a water/organic mixture has been developed to address formulation issues resulting from a water sensitive, high drug load API with poor powder properties. Initially, the API is dissolved in water, following which hydroxypropyl methylcellulose (HPMC) is added, resulting in the imbibing of water, along with the dissolved API, into the HPMC matrix. The addition of acetone and isopropyl acetate (anti-solvents) then causes the API to crystallize inside and on the surface of HPMC agglomerates. The process was scaled up to 20 kg scale. The agglomerates of API and HPMC generated by this process are ∼350 µm diameter, robust, and have significantly better flow than the API as measured by Erweka flow testing. These agglomerates exhibit improved bulk density, acceptable chemical stability, and high compressibility. The agglomerates process well through roller compaction and tableting, with no flow or sticking issues. This process is potentially adaptable to other APIs with similar attributes.

Active pharmaceutical ingredient (API) particle size distribution is important for both downstream processing operations and in vivo performance. Crystallization process parameters and reactor configuration are important in controlling API particle size distribution (PSD). Given the large number of parameters and the scale-dependence of many parameters, it can be difficult to design a scalable crystallization process that delivers a target PSD. Population balance modeling is a useful tool for understanding crystallization kinetics, which are primarily scale-independent, predicting PSD, and studying the impact of process parameters on PSD. Although population balance modeling (PBM) does have certain limitations, such as scale dependency of secondary nucleation, and is currently limited in commercial software packages to one particle dimension, which has difficulty in predicting PSD for high aspect ratio morphologies, there is still much to be gained from applying PBM in API crystallization processes.