Stabilizers used in nanocrystal based drug delivery systems

Nanocrystals have emerged as a viable tool to enhance oral bioavailability of poorly water soluble drugs. They also enable parenteral administration of these drugs as nanosuspensions. The high surface free energy due to the large surface area to volume ratio of nanocrystals, makes them prone to aggregation, that can lead to physical instability and loss of solubility/dissolution advantage. Stabilizers are incorporated into nanocrystalline formulations to prevent aggregation and these include excipients such as polymers and surfactants. They achieve stabilization by electrostatic repulsion and/or steric hindrance. This article focuses on phenomenon of aggregation in nanocrystal based formulations, stabilizers for inhibition of aggregation, classification of stabilizers, properties of stabilizers and the mechanisms involved in stabilization. A compilation of stabilizers, drugs stabilized, formulation types and techniques used for generation of nanocrystals have been presented. Current challenges and future trends in the field of stabilizers have also been highlighted

Quantification of clarithromycin polymorphs in presence of tablet excipients

Excipients can cause a considerable challenge when developing a solid form of an active pharmaceutical ingredient (API). The aim of this present study was to analyze the polymorphs of clarithromycin (CAM) mixed with excipients using powder X-ray diffraction (PXRD). Polymorphic Form I (CAM-1), Form II (CAM-2) and an amorphous phase of CAM were characterized using thermal and crystallographic methods. CAM-1 and CAM-2 were monotropically related, with CAM-2 being the stable form. PXRD instrument related parameters were optimized for the characterization of CAM polymorphic forms using a variety of excipients. Calibration curves for CAM-1 and CAM-2 mixed with excipients were also prepared. Analytical methods based on the differences in the diffraction patterns of CAM-1, CAM-2 and the excipients were developed. Sodium methyl paraben, sodium propyl paraben, microcrystalline cellulose and magnesium stearate were crystalline showing characteristic diffraction patterns. Starch, croscarmellose sodium, talc and sodium starch glycolate were semicrystalline in nature, while colloidal silicon dioxide was amorphous. A diffraction peak at 8.7° 2θ provided a quantification of CAM-2 when mixed with excipients. The analytical method was evaluated and validated for accuracy, precision, inter- and intra-day variation, variability due to sample repacking and instrument reproducibility. The method for quantification of CAM-2 in the range of 80 to 100% w/w was linear with R2 = 0.998. Relative standard deviation (RSD), due to sample repacking, was 2.77% indicating good homogeneity of mixing of the samples. RSD due to assay errors was 1.66%. PXRD analysis of the commercial tablet showed the CAM-2 as a major polymorph being 98% of the overall content of the API. CAM-1 was found to be present as an impurity at trace levels shown by peaks at 2θ values of 5.2° and 6.7°. This method provides a method for characterization of the polymorphic forms of CAM in the presence of commonly used excipients. It could be a useful tool for monitoring solid form behavior during product development and stability studies

Simultaneous Estimation & Validation of Praziquantel & Pyrantel Pamoate in Bulk & Pharmaceutical Dosage Form by Using RP-HPLC

The first reversed phase high performance liquid chromatographic method for quantitation studies  of, Praziquantel and Pyrantel Pamoate has been developed and validated to be a simple, sensitive, rapid, specific, precise, and accurate method. Chromatographic separation was achieved on C18 column (250×4.6 mm-5μm p.s). Methanol and water in a ratio [85:15 v/v] as a mobile phase at flow rate of 0.8ml/min. UV detection was operated at 217 nm and injection volum was 20 μl.. The proposed method showed good linearity, accuracy, precision and was successfully applied for determination of the drugs in laboratory prepared pharmaceutical dosage forms. The current method has been statistically validated according to the ICH guidelines and this method has been subsequently developed and applied successfully to determine the levels of Praziquantel and Pyrantel pamoate in a combined formulation and in the routine quality control analysis with good accuracy and sensitivity. Keywords: Praziquantel, Pyrantel pamoate, Quantitation Studies,   RP-HPLC

Drug-excipient behavior in polymeric amorphous solid dispersions

Amorphous drug delivery systems are increasingly utilized to enhance aqueous solubility and oral bioavailability. However, they lack physical and/or chemical stability. One of the most common ways of stabilizing an amorphous form is by formulating it as an amorphous solid dispersion. This review focuses on polymeric amorphous solid dispersions wherein polymers are used as excipients to stabilize the amorphous form. A brief introduction to the basic concepts of amorphous systems such as glass transition temperature and the solubility advantage of amorphous systems is provided. Additionally, information on types of polymers used for the development of amorphous solid dispersions, their structural attributes and mechanisms of stabilization are presented here. Molecular aspects of drug-polymer miscibility and drugpolymer interactions are also discussed

Multiple Loci Are Associated with White Blood Cell Phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds

Quantification of clarithromycin polymorphs in presence of tablet excipients

Characterization of solid form of API in presence of excipients offers considerable challenge. Aim of the present study was to quantify polymorphs of clarithromycin (CAM) in a commercial tablet in the presence of excipients, by powder X-ray diffraction (PXRD) method. Polymorphic Form I (CAM-1), Form II (CAM-2) and amorphous phase of CAM were characterized using thermal and crystallographic tools. CAM-1 and CAM-2 were found to be monotropically related, with CAM-2 being the stable form. PXRD instrument related parameters were optimized for characterization of CAM polymorphic forms in a mixture of excipients. Calibration curves for CAM-1 and CAM-2 were prepared in a mixture with excipients. Analytical method based on differences in diffraction pattern of CAM-1, CAM-2 and excipients was developed. Sodium methyl paraben, sodium propyl paraben, microcrystalline cellulose and magnesium stearate were crystalline and exhibited characteristic diffraction pattern. Starch, croscarmellose sodium, talc and sodium starch glycolate were found to be semicrystalline in nature while colloidal silicon dioxide was amorphous material. Diffraction peak at 8.7° 2θ value allowed quantification of CAM-2 in the presence of excipients. The analytical method was evaluated and validated for accuracy, precision, inter and intraday variation, variability due to sample repacking and instrument reproducibility. The method for quantification of CAM-2 in the range of 80 to 100% w/w was found to be linear with R2 = 0.998.  Relative standard deviation (RSD) due to sample repacking was 2.77% indicating good homogeneity of mixing of samples. RSD due to all assay errors was found to be 1.66%. PXRD analysis of commercial tablet revealed presence of CAM-2 as major polymorph and it was found to be 98% of the overall content of API. CAM-1 was found to be present as an impurity in trace amount as evidenced by peaks at 2θ values of 5.2° and 6.7°. This method allows characterization of polymorphic forms of CAM in presence of common tablet excipients. It can be a useful tool for monitoring solid form behavior during product development and stability studies.

ALTERNATIVE ENERGY SOURCEFOR AUTOMOBILE VEHICLE

Alternate energy source of magnetic levitation propulsion used in automobile, with self-generation of electricity for charging the battery. This is a four wheel vehicle with drive mechanism being propelled by the magnetic levitation which is used in maglev trains. Here the piston is moving within the coil to effect the to and fro motion when energized, to effect the cranking and rotations which drives the vehicle. The control circuit is provided for giving the acceleration, the batteries are provided for the control circuit and the battery meant for energizing the coils is to be arranged externally

Oral Bioavailability and Pharmacodynamic Activity of Hesperetin Nanocrystals Generated Using a Novel Bottom-up Technology

In the present study, nanocrystalline solid dispersion (NSD) was developed to enhance the release rate and oral bioavailability of hesperetin (HRN). NSD of HRN was prepared using a novel bottom-up technology platform. It is a spray drying based technology to generate solid particles, containing drug nanocrystals dispersed in small molecule excipients. HRN and mannitol were used in a 5:5 ratio, and an average crystallite size of HRN in NSD with mannitol was found to be 137.3 ± 90.0 nm. An <i>in vitro</i> release study revealed a statistically significant release rate enhancement for HRN nanocrystals (46.3 μg/mL/min) as compared to that of the control (29.5 μg/mL/min). Further, a comparative oral bioavailability study of NSD and control in Sprague–Dawley rats established significant improvement in <i>C</i>_max and oral bioavailability (AUC_0–∞) by 1.79- and 2.25-fold, respectively, for HRN nanocrystals. The findings of oral bioavailability were corroborated by intestinal uptake and Caco-2 cell uptake studies, wherein HRN, when administered in nanocrystalline form, showed higher penetration in intestinal mucosa and higher uptake in Caco-2 cells. Finally, the therapeutic efficacy of HRN nanocrystals was tested by a reactive oxygen species (ROS) generation assay and carrageenan induced anti-inflammatory model. HRN nanocrystals markedly inhibited ROS generation in MCF-7 cells, and carrageenan induced inflammation in rats. The process of NSD formation was found to be based on classical nucleation theory wherein mannitol contributed to NSD formation by acting as a plasticizer and crystallization inducer, and by providing sites for heterogeneous nucleation/crystallization