Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.

We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

Microdialysis and nanofiltration allow to distinguish molecularly dissolved from colloid-associated drug concentrations during biomimetic dissolution testing of supersaturating formulations.

Many new drug entities are poorly water-soluble and thus require solubility-enhancing formulations to ensure sufficient bioavailability. On the other hand, it is more and more accepted that not all "dissolved" states of a drug contribute equally to enhanced absorption, i.e. an increase in apparent solubility does not necessarily go in parallel with an increase in molecularly dissolved drug, the latter being regarded as the key driving force for absorption. Our study aimed to provide time-resolved information on the dissolution, supersaturation, and precipitation behavior of molecularly dissolved drug as released from an amorphous solid dispersion and a surfactant-containing crystalline suspension of Posaconazole (PCZ), a weakly basic and poorly water-soluble drug. Thereby, we aimed to gain a deeper mechanistic understanding of enabling formulation principles and possibly establish a dynamic biopharmaceutical assessment tool for molecularly dissolved drug released from enabling formulations. A two-staged dissolution test, with media transition from simulated gastric fluid (SGF) to fasted state simulated intestinal fluid (FaSSIF), was performed with three alternative sampling approaches in parallel: the classical bench centrifugation approach was used to assess total dissolved concentrations, while a nanofiltration method and a microdialysis setup were tested for their ability to discriminate molecularly and colloid-associated drug concentrations over time. For comparison, a single-stage dissolution setup was performed, where a marketed PCZ suspension was dispersed in biomimetic media with increasing amounts of solubilizing agents to understand their effect on the concentration of molecularly dissolved drug. It was demonstrated that the microdialysis setup allowed to follow the molecularly dissolved drug concentration in a time-resolved manner during the single-and two-stage dissolution tests with marginal delays. Interestingly, the PCZ concentrations measured by the nanofiltration approach differed from both, the molecularly dissolved (assessed by microdialysis) and apparently dissolved (assessed by centrifuge) PCZ concentrations, indicating that nanofiltration may allow to differentiate between different colloid-associated (apparently) dissolved drug species. Moreover, it was shown that the release of the molecularly dissolved drug from an amorphous solid dispersion did not correlate at all with the results obtained by the centrifugation method: While this conventional sampling revealed a classical spring and parachute concentration/time-profile with a high degree of (apparent) supersaturation, the concentration of molecularly dissolved drug (assessed by the microdialysis setup) indicated an initial short decline of PCZ concentration, followed by a prolonged (moderate) molecular supersaturation. This observation may give rise to a re-thinking of the current mechanistic understanding of how amorphous solid dispersions enhance oral bioavailability. In essence, the current study provides data which indicate a benefit of both the microdialysis sampling and nanofiltration approaches for the in vitro biopharmaceutical assessment of enabling drug formulations.

Factors and dosage formulations affecting the solubility and bioavailability of P-glycoprotein substrate drugs.

Introduction: Expression of P-glycoprotein (P-gp) increases toward the distal small intestine, implying that the duodenum is the preferential absorption site for P-gp substrate drugs. Oral bioavailability of poorly soluble P-gp substrate drugs is low and varied but increases with high-fat meals that supply lipoidal components and bile in the duodenum.Areas covered: Absorption properties of P-gp substrate drugs along with factors and oral dosage formulations affecting their solubility and bioavailability were reviewed with PubMed literature searches. An overview is provided from the viewpoint of the 'spring-and-parachute approach' that generates supersaturation of poorly soluble P-gp substrate drugs.Expert opinion: The oral bioavailability of P-gp substrate drugs is difficult to predict because of their low solubility, preferential absorption sites, and overlapping substrate specificities with CYP3A4, along with the scattered intestinal P-gp expression/function. To attain high and steady oral bioavailability of poorly soluble P-gp substrate drugs, physicochemical modification of drugs to improve solubility, or oral dosage formulations that generate long-lasting supersaturation in the duodenum, is preferred. In particular, supersaturable lipid-based drug delivery systems that can increase passive diffusion and/or lymphatic absorption are effective and applicable to many poorly soluble P-gp substrate drugs.

Cryogenic Fabrication of Dry Powders to Enhance the Solubility of a Promising Anticancer Drug, SHetA2, for Oral Administration.

SHetA2 is a novel anticancer drug with poor aqueous solubility. In formal toxicological studies, Kolliphor HS 15 was used as a solubilizing agent to increase the oral bioavailability of SHetA2. The purpose of this study was to formulate SHetA2 and Kolliphor HS 15 as solid powders to facilitate their filling in hard gelatin capsules for clinical trials. Two manufacturing processes, ultra-rapid freeze-drying (URFD) and spray freeze drying (SFD), were employed to fabricate solid powders of SHetA2-Kolliphor HS 15 and trehalose. The morphology, size, flowability, and compressibility of URFD-SHetA2 and SFD-SHetA2 powders were characterized. The crystallinity and apparent maximum solubility of SHetA2 in both powders were also determined. SFD-SHetA2 powders were spherical in shape, small, and with a wide size distribution while the URFD-SHetA2 powders were irregularly shaped and big but with a narrower distribution. DSC and XRD analyses indicated that SHetA2 was mostly amorphous in both powders. The flow of both powders was categorized as "good" (angle of repose < 35°). The uniformity of drug content in URFD-SHetA2 powders was more variable than that in SFD-SHetA2 powders. The solubility profile of SHetA2 in both powders SGF exhibited a transient supersaturation "spring effect" due to the drug's amorphousness followed by extended supersaturation "parachute effect" at approximately 6 µg/ml for both powders compared to 0.02 ± 0.01 µg/ml for unprocessed drug. In conclusion, both URFD and SFD formed solid SHetA2 Kolliphor powders that are possible formulation candidates to be filled in hard gelatin capsules for clinical trials.