Category: Formulation and Quality
Purpose: KinetiSol® is a high-energy, fusion-based technology utilized to enhance the solubility of poorly water soluble drugs by generating stable amorphous solid dispersions (ASDs) of drug-polymer systems. In addition, KinetiSol® is a solvent-free processing method and processes drug-polymer blends at an order of magnitude of mixing greater than hot melt extrusion (HME) without requiring thermal energy input. Conversely, spray drying is a well-understood solvent-based ASD processing technology and relies on drug and polymer solubility in a common solvent for processing. Historically, industry has relied on HME or spray drying to produce ASDs, but KinetiSol® has shown promise in recent literature, and thus, KinetiSol® should be evaluated as a suitable alternative for generating stable ASDs. Notably, understanding the effect of a manufacturing process on ASD particle properties (e.g., morphology, porosity, surface area, dissolution) is required. Therefore, the purpose of this study was to prepare KinetiSol® solid dispersions and spray dried dispersions at equivalent formulation composition to evaluate the ASD particles produced and better understand their effect on dissolution.
Methods: A BCS Class IV molecule synthesized by Boeheringer Ingelheim, BI 639667 (BI 667), which is a weak base that exhibits pH-dependent solubility, was selected for evaluation. An enteric polymer was selected (Shin Etsu’s AQOAT, HPMCAS-MMP), and the selected drug-polymer ratio was 1:2 (based on previous studies).
KinetiSol® was conducted by charging the BI 667-HPMCAS-MMP (1:2) powder blend into a KinetiSol® Formulator chamber, and the parameters used were an ejection temperature of 160˚C and a mixing speed of 4,500 rpm. Once the set-point ejection temperature was reached, the sample was ejected and immediately quenched between two aluminum plates. The processed material was milled and passed through a 125 µm sieve and collected on a 75 µm sieve. The material collected was labeled KinetiSol® solid dispersion (KSD).
Spray drying was conducted using a Büchi B-290 Mini Spray Dryer at an inlet temperature of 78˚C after dissolving BI 667 and HPMCAS-MMP (1:2) at 3.33% w/v in an acetone:water (9:1 v/v) solution. Secondary drying occurred overnight in a vacuum oven. The collected product was labeled spray dried dispersion (SDD).
Following processing, powder X-ray diffraction (PXRD) was utilized to characterize amorphicity of samples, Brunauer-Emmett-Teller (BET) theory was used to characterize particle specific surface area (SSA), and scanning electron microscopy (SEM) was employed to understand particle morphologies. Small-volume pH-dilution dissolution was conducted using a USP Apparatus 2 with a paddle speed of 100 rpm by adding 40 mg equivalents of BI 667 to 90 mL 0.01 N hydrochloric acid for 30 min. At t=30 min, 60 mL of fasted state simulated intestinal fluid (FaSSIF) in pH 6.8 0.1 M phosphate buffer was added to the dissolution vessel. At specific time points, samples were collected, filtered, and BI 667 concentration in solution was evaluated by high performance liquid chromatography (HPLC).
Results: The processing time of the KSD was < 22 s, and both KSD and SDD particles were confirmed amorphous by PXRD. However, substantial differences in particle morphology were observed by calculated SSA values and SEM. KSD particles had 10% the SSA of the SDD particles. SEM provided a better understanding of this finding, where KSD particles were dense and non-porous, while SDD particles were small and extremely porous.
The porosity and SSA differences observed helped better explain the dissolution behavior of the KSD and SDD particles (Figure 1). During the acid phase of dissolution, due to the porosity of the SDD particles, the dissolution media was able to solubilize amorphous BI 667 from channels of HPMCAS-MMP even though the HPMCAS-MMP had not solubilized. Upon addition of basic media, the BI 667 concentration became appreciably reduced and slowly precipitated towards equilibrium solubility. Conversely, due to the density and relative non-porosity of the KSD particles, very little dissolution occurred until after the polymer ionized and hydrated (t≥30 min). The KSD particles’ % release Cmaxwas 147% of the SDD particles % release Cmax,because release occurred in a larger volume of media (i.e., the Cmaxoccurred in 150 mL for KSD particles, whereas the Cmaxoccurred in 90 mL for SDD particles). By calculating the total area under the dissolution curve (AUDC), the SDD and KSD particles had nearly identical values. However, by calculating the AUDC during the basic phase (which may simulate the absorption phase of intestinal transit), the KSD particles exhibited an AUDC of 126% of the SDD particles’ AUDC from t=30 to 120 min, and after 120 min, the AUDCs were essentially identical.
Conclusion: Processing differences between a fusion-based (KinetiSol®) and solvent-based (spray drying) processing technology resulted in substantially different ASD particles, which ultimately affected the dissolution behavior of the particles in a biorelevant pH-dilution method. In this study, the KinetiSol® technology produced ASD particles that exhibit better release in biorelevant pH-dilution dissolution than when compared with a compositionally equivalent spray dried ASD product.
Michael Lowinger– Graduate Student, Merck & Co., Inc., Rahway, New Jersey
Dave Miller– Vice President; Research & Development, DisperSol Technologies, Georgetown, Texas
Robert Williams– Division Head, The University of Texas at Austin, Austin, Texas