RESUMO
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 â¼350 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.
Assuntos
Química Farmacêutica/métodos , Derivados da Hipromelose/síntese química , Derivados da Hipromelose/farmacocinética , Cristalização , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/farmacocinética , Composição de Medicamentos , Liberação Controlada de FármacosRESUMO
Microtiter plate assay is a conventional and standard tool for high-throughput (HT) screening that allows the synthesis, harvesting, and analysis of crystals. The microtiter plate screening assays require a small amount of solute in each experiment, which is adequate for a solid-state crystal analysis such as X-ray diffraction (XRD) or Raman spectroscopy. Despite the advantages of these high-throughput assays, their batch operational nature results in a continuous decrease in supersaturation due to crystal nucleation and growth. Continuous-flow microfluidic mixer devices have evolved as an alternate technique for efficiently screening crystals under controlled supersaturation. However, such a microfluidic device requires a minimum of two inlets per micromixer to create cyclonic flow, thereby creating physical limitations for implementing such a device for HT screening. Additionally, the monolithic design of these microfluidic devices makes it challenging to harvest crystals for post-screening analysis. Here, we develop a snap-on adapter that can be reversibly attached to a microtiter plate and convert it into a continuous-flow microfluidic mixer device. The integration of the snap-on adapter with a flow distributor and concentration gradient generator provides greater control over screening conditions while minimizing the number of independent inlets and pumps required. The three-dimensional (3D)-printed snap-on adaptor is plugged into a 24-well plate assay to demonstrate salt screening of naproxen crystals. Different naproxen salts are crystallized using four different salt formers (SFs)-sodium hydroxide, potassium hydroxide, pyridine, and arginine-and four different solvents-ethanol, methanol, isopropyl alcohol, and deionized water. The wells are further inspected under an optical microscope to identify their morphological forms and yields. The crystals are then harvested for solid-state characterization using XRD and Fourier transform infrared spectroscopy, followed by measurement of their dissolution rates. The flexibility of the snap-on adapter to fit on a wide range of microtiter plates and the ease in harvesting and analyzing crystals postscreening are two significant advantages that make this device versatile for various applications.
RESUMO
Metal-organic frameworks (MOFs) are porous crystalline structures that are composed of coordinated metal ligands and organic linkers. Due to their high porosity, ultra-high surface-to-volume ratio, and chemical and structural flexibility, MOFs have numerous applications. MOFs are primarily synthesized in batch reactors under harsh conditions and long synthesis times. The continuous depletion of metal ligands and linkers in batch processes affects the kinetics of the oligomerization reaction and, hence, their nucleation and growth rates. Therefore, the existing screening systems that rely on batch processes, such as microtiter plates and droplet-based microfluidics, do not provide reliable nucleation and growth rate data. Significant challenges still exist for developing a relatively inexpensive, safe, and readily scalable screening device and ensuring consistency of results before scaling up. Here, we have designed patterned-surface microfluidic devices for continuous-flow synthesis of MOFs that allow effective and rapid screening of synthesis conditions. The patterned surface reduces the induction time of MOF synthesis for rapid screening while providing support to capture MOF crystals for growth measurements. The efficacy of the continuous-flow patterned microfluidic device to screen polymorphs, morphology, and growth rates is demonstrated for the HKUST-1 MOF. The effects of solvent composition and pH modulators on the morphology, polymorphs, and size distribution of HKUST-1 are evaluated using the patterned microfluidic device. Additionally, a time-resolved FT-IR analysis coupled with the patterned microfluidic device provides quantitative insights into the non-monotonic growth of MOF crystals with respect to the progression of the bulk oligomerization reaction. The patterned microfluidic device can be used to screen crystals with a longer induction time, such as proteins, covalent-organic frameworks, and MOFs.