Considerations for the selection of co-formers in the preparation of co-amorphous formulations.

Co-amorphous drug delivery systems are evolving as a credible alternative to amorphous solid dispersions technology. In Co-amorphous systems (CAMs), a drug is stabilized in amorphous form using small molecular weight compounds called as co-formers. A wide variety of small molecular weight co-formers have been leveraged in the preparation of CAMs. The stability and supersaturation potential of prepared co-amorphous phases largely depend on the type of co-former employed in the CAMs. However, the rationality behind the co-former selection in co-amorphous systems is poorly understood and scarcely compiled in the literature. There are various facets to the rational selection of co-former for CAMs. In this context, the present review compiles various factors affecting the co-former selection. The factors have been broadly classified under Thermodynamic, Kinetic and Pharmacokinetic-Pharmacologically relevant parameters. In particular, the importance of Glass transition, Miscibility, Liquid-Liquid phase separation (LLPS), Crystallization inhibition has been deliberated in detail.

Dronedarone HCl-Quercetin Co-Amorphous System: Characterization and RP-HPLC Method Development for Simultaneous Estimation.

BACKGROUND: Dronedarone HCl (DRN) is an anti-arrhythmic drug indicated for atrial fibrillation. DRN has a low solubility of 2 µg/mL and 4% bioavailability, thus it is formulated as a co-amorphous system to enhance its solubility by using quercetin (QCT) as a co-former. A sensitive, accurate, and economic method for the simultaneous quantification of DRN and QCT in formulation is not found in the literature. OBJECTIVE: To develop a Reverse Phase -HPLC method for the simultaneous estimation of DRN and QCT in a DRN-QCT co-amorphous system. METHOD: The co-amorphous system was prepared using a solvent evaporation technique with DRN and QCT in a 1:1 molar ratio. The separation was achieved on a Purospher® STAR C18 (250 mm × 4.6 mm × 5 µm id (internal diameter)) column with the mobile phase comprising of acetonitrile and a 25 mM phosphate buffer pH 3.6 (60:40%, v/v). RESULTS: DRN and QCT were retained on the column for 6.7 and 3.5 min, respectively. For both molecules, the method was developed with a wide linearity range of 0.2-500 µg/mL. The LOD for DRN was found to be 0.0013 µg/mL and for QCT it was found to be 0.0026 µg/mL. The LOQ for DRN was found to be 0.0041 µg/mL, and for QCT it was 0.0078 µg/mL. CONCLUSIONS: The method was validated as per International Conference on Harmonization (ICH) guidelines for linearity, precision, accuracy, and robustness. The method was used in simultaneous quantification of DRN and QCT in co-amorphous samples. HIGHLIGHTS: The method developed was used for the analysis of content uniformity and solubility samples of co-amorphous system, where the method was able to successfully quantify DRN and QCT. Low detection and quantification limits contribute to the sensitivity of the method and wide linearity range assures the robust and precise quantification of molecules.

Overview of Extensively Employed Polymeric Carriers in Solid Dispersion Technology.

Solid dispersion is the preferred technology to prepare efficacious forms of BCS class-II/IV APIs. To prepare solid dispersions, there exist a wide variety of polymeric carriers with interesting physicochemical and thermochemical characteristics available at the disposal of a formulation scientist. Since the advent of the solid dispersion technology in the early 1960s, there have been more than 5000 scientific papers published in the subject area. This review discusses the polymeric carrier properties of most extensively used polymers PVP, Copovidone, PEG, HPMC, HPMCAS, and Soluplus® in the solid dispersion technology. The literature trends about preparation techniques, dissolution, and stability improvement are analyzed from the Scopus® database to enable a formulator to make an informed choice of polymeric carrier. The stability and extent of dissolution improvement are largely dependent upon the type of polymeric carrier employed to formulate solid dispersions. With the increasing acceptance of transfer dissolution setup in the research community, it is required to evaluate the crystallization/precipitation inhibition potential of polymers under dynamic pH shift conditions. Further, there is a need to develop a regulatory framework which provides definition and complete classification along with necessarily recommended studies to characterize and evaluate solid dispersions.

The relevance of co-amorphous formulations to develop supersaturated dosage forms: In-vitro, and ex-vivo investigation of Ritonavir-Lopinavir co-amorphous materials.

Ritonavir and Lopinavir have previously been demonstrated to decrease the maximum solubility advantage and flux in the presence of each other. The present study investigated the ability of Ritonavir and Lopinavir co-amorphous materials to generate a supersaturated state. Further, it explored the precipitation and flux behavior of co-amorphous materials. The co-amorphous materials of Ritonavir and Lopinavir were prepared by quench cool method and characterized in the solid state using XRPD, DSC, FTIR. The solubility studies were conducted in USP phosphate buffer (pH 6.8) for 12 h. The supersaturation potential and precipitation behavior were studied employing pH shift method. Further, the diffusion behavior was explored in vitro and ex-vivo using a semipermeable membrane and intestinal everted sac method, respectively. The results showed that the co-amorphous materials have the potential to generate a supersaturated state. However, the reduction in the amorphous solubility was observed for both the drug(s) and the degree of reduction was found proportionate with the mole fraction of the compound in the co-amorphous material. Interestingly, the flux of both the drugs from co-amorphous material of 2:1 M ratio (Ritonavir 2: Lopinavir 1) was found exceeding the flux of the individual drugs in the amorphous form. The significant increase in the flux was attributed to the improved drug release properties due to precipitation of drug rich phase of nano/micro dimensions.

Assessment, validation and deployment strategy of a two-barcode protocol for facile genotyping of duckweed species.

Lemnaceae, commonly called duckweeds, comprise a diverse group of floating aquatic plants that have previously been classified into 37 species based on morphological and physiological criteria. In addition to their unique evolutionary position among angiosperms and their applications in biomonitoring, the potential of duckweeds as a novel sustainable crop for fuel and feed has recently increased interest in the study of their biodiversity and systematics. However, due to their small size and abbreviated structure, accurate typing of duckweeds based on morphology can be challenging. In the past decade, attempts to employ molecular barcoding techniques for species assignment have produced promising results; however, they have yet to be codified into a simple and quantitative protocol. A study that compiles and compares the barcode sequences within all known species of this family would help to establish the fidelity and limits of this DNA-based approach. In this work, we compared the level of conservation between over 100 strains of duckweed for two intergenic barcode sequences derived from the plastid genome. By using over 300 sequences publicly available in the NCBI database, we determined the utility of each of these two barcodes for duckweed species identification. Through sequencing of these barcodes from additional accessions, 30 of the 37 known species of duckweed could be identified with varying levels of confidence using this approach. From our analyses using this reference dataset, we also confirmed two instances where mis-assignment of species has likely occurred. Potential strategies for further improving the scope of this technology are discussed.