Oral medicines must release the drug appropriately in the GI tract in order to assure adequate and reproducible absorption. Disease states and co-administration of drugs may alter GI physiology and therefore the release profile of the drug. Acid-reducing agents (ARAs), especially proton pump inhibitors (PPIs), are frequently co-administered during various therapies. As orally administered drugs are frequently poorly soluble weak bases, PPI co-administration raises the risk of pH-induced drug-drug interactions (DDIs) and the potential for changes in the therapeutic outcome.
 
  This research compared the dissolution data of a poorly soluble weakly basic drug ("PSWB 001") from capsules in standard fasted state biorelevant media (FaSSGF, FaSSIF V1 and FaSSIF V2), water and recently devised media representing gastric conditions under various levels of PPI co-administration. An in silico simulation model, based on Simcyp software, was developed to compare simulated plasma profiles with clinical data.
 
  PSWB 001 caombined with PBPK modeling, were able to bracket the observed plasma profiles of PSWB 001. These media may also be useful for predicting PPI effects for other poorly soluble, weakly basic drugs.Anti-inflammatory drugs have been prescribed extensively for a wide range of diseases. Combined with over-the-counter use, approximately 30 billion doses of non-steroidal inflammatory drugs (NSAIDs) are consumed annually in the USA. The global market of glucocorticoids (GCs) is forecast to reach US$ 8.6 billion by 2025. Severe adverse effects have been reported for NSAIDs, GCs, and COX-2 selective NSAIDs (COXIBs). Furthermore, the overwhelming majority of these drug substances are BCS class II, which limits their bioavailability due to poor water solubility. Drug nanocrystals, a carrier-free nanosystem, can increase saturation solubility, dissolution rate, and the mucoadhesiveness of these drugs. The enhancement of these properties was highlighted in our findings. These features improve the efficacy and safety of anti-inflammatory drugs. In this review, we show that drug nanocrystals are an attractive strategy that contributes to an important shift in the development of innovative products for different routes of administration. The possibility of targeting can minimize the adverse effects and improve the efficacy in the management of inflammatory conditions. We comprehensively review the critical quality attributes (CQAs) in the anti-inflammatory drug nanocrystals preparation, which are fundamental to developing a successful marketable product. Despite the advantages, maintaining properties such as average particle size, surface properties, and physicochemical stability of these preparations during shelf life poses challenges to be overcome.An industrially feasible approach to overcome the solubility and bioavailability limitations of poorly soluble active pharmaceutical ingredients is the development of amorphous solid dispersions (ASDs) using hot-melt extrusion (HME) technique. The application of Quality by Design (QbD) had a profound impact on the development of HME-based ASDs. The formulation and process optimization of ASDs manufactured via HME techniques require an understanding of critical quality attributes, critical material attributes, critical process parameters, risk assessment tools, and experimental designs. The knowledge gained from each of these QbD elements helps ensure the consistency of product quality. The selection and implementation of appropriate Design of Experiments (DoE) methodology to screen and optimize the formulation and process variables remain a major challenge. This review provides a comprehensive overview on QbD concepts in HME-based ASDs with an emphasis on DoE methodologies. Further, the information provided in this review can assist researchers in selecting a suitable design with optimal experimental conditions. Specifically, this review has focused on the prediction of drug-polymer miscibility, the elements and sequence of QbD, and various screening and optimization designs, to provide insights into the formulation and process variables that are encountered routinely in the production of HME-based ASDs.New synthetic compound Raptinal (RAP) was investigated on different biological levels for its potential anticancer activity. RAP showed higher antiproliferative activity on HepG2 cell line with IC50 0.62µM compared to MCF-7 and HCT-116 (4.03 and 92.3 µM) respectively. Moreover, RAP induces early stage of apoptosis in the most sensitive HepG2 treated cells after 24 hr with cell cycle arrest in both subG0-G1 and G0-G1 phases and minimal cell count in G2/M mitotic phase with apoptotic index 9.25-fold higher than to control. RAP induces over-expression of key apoptotic genes such as Fas receptor, Caspase-8, Caspase-9, Bax and P53. Western blotting confirm the observation on protein level via over-expression of Caspase-9, Cytochrome-C and higher ration of Bax/Bcl-2. In addition, RAP was radiolabeled using one of the most important diagnostic radioactive isotopes, technetium-99m (99mTc), with a radiochemical yield of 92.7 ± 0.41 %. Quality control and biological distribution of 99mTc-RAP in both healthy and HCC rat model were investigated. Biodistribution profile revealed the localization of RAP in liver tissues (20.5±2.6 %) of HCC models at half an hour post intravenous injection. Histopathological examination confirmed the biodistribution of RAP into liver tissue with induction of karyomegaly in the nuclei of hepatocytes as well as others that proceeded into apoptosis. Molecular docking suggested RAP binds in binding pocket of p53 cancer mutant Y220C making reactivation of the mutant form which is a promising strategy for further investigation on molecular level as a novel anticancer therapeutics. All the results support the use of RAP as a potential anticancer drug in HCC and its 99mTc complex as an imaging probe.Further optimization of the VU0486321 series of highly selective and CNS-penetrant mGlu1 PAMs identified unique 'molecular switches' on the central aromatic ring that engendered positive cooperativity with multiple mGlu subtypes across the receptor family, resulting in compounds with comparable activity at Group I (mGlu1/5) and Group III (mGlu4/6/7/8) mGlu receptors, receptors.  https://www.selleckchem.com/products/l-monosodium-glutamate-monohydrate.html  These exciting data suggests this PAM chemotype appears to bind to multiple mGlu receptors, and that subtype selectivity is dictated by the degree of cooperativity, not a subtype selective, unique allosteric binding site. Moreover, there is interesting therapeutic potential for mGlu1/4/7/8 PAMs, as well as the first report of a GPCR allosteric 'privileged structure'.