3-Carboxy-cis,cis-muconate lactonizing enzymes (CMLEs), the key enzymes in the protocatechuate branch of the beta-ketoadipate pathway in microorganisms, catalyze the conversion of 3-carboxy-cis,cis-muconate to muconolactones. We have determined the crystal structure of the prokaryotic Pseudomonas putida CMLE (PpCMLE) at 2.6 A resolution. PpCMLE is a homotetramer and belongs to the fumarase class II superfamily. The active site of PpCMLE is formed largely by three regions, which are moderately conserved in the fumarase class II superfamily, from three respective monomers. It has been proposed that residue His141, which is highly conserved in all fumarase class II enzymes and forms a charge relay with residue Glu275 (both His141 and Glu275 are in adenylosuccinate lyase numbering), acts as the general base in most fumarase class II superfamily members. However, this charge relay pair is broken in PpCMLE. The residues corresponding to His141 and Glu275 are Trp153 and Ala289, respectively, in PpCMLE. The structures of prokaryotic MLEs and that of CMLE from the eukaryotic Neurospora crassa are completely different from that of PpCMLE, indicating MLEs and CMLEs, as well as the prokaryotic and eukaryotic CMLEs, evolved from distinct ancestors, although they catalyze similar reactions. The structural differences may be related to recognition by substrates and to differences in the mechanistic pathways by which these enzymes catalyze their respective reactions.
The regulatory requirements of various countries of the world vary from each other. Therefore, it is challenging for the companies to develop a single drug which can be simultaneously submitted in all the countries for approval. The regulatory strategy for product development is essentially to be established before commencement of developmental work in order to avoid major surprises after submission of the application. The role of the regulatory authorities is to ensure the quality, safety, and efficacy of all medicines in circulation in their country. It not only includes the process of regulating and monitoring the drugs but also the process of manufacturing, distribution, and promotion of it. One of the primary challenges for regulatory authority is to ensure that the pharmaceutical products are developed as per the regulatory requirement of that country. This process involves the assessment of critical parameters during product development.
A simple, accurate, precise, sensitive, selective, and stability-indicating high-performance thin-layer chromatographic method was developed and validated for determination of duloxetine hydrochloride both in bulk drug as well as in tablet formulation. The stationary phase used in our method consisted of HPTLC aluminum plates precoated with silica gel 60F-254, while, chloroform : methanol (8 : 2, v/v) was used as binary mobile phase. These chromatographic conditions eluted the drug effectively, and distinct compact spots were seen, (Rf, retardation factor, value (0.42 ± 0.20). Densitometric determination of duloxetine hydrochloride was carried out in the absorbance mode at a wavelength of 217 nm. The mean value of corelation coefficient; slope and intercept were 0.9962 ± 0.0015, 121.54 ± 0.61, and 987.3 ± 6.17, in the amount range of 600–2000 ng (nanogram) per spot, respectively. Stress testing validation were performed as per the guidelines of International Conference on Harmonization (ICH) and drug was subjected to stress conditions like acid-hydrolysis, alkali-hydrolysis, oxidation, and thermal degradation. As the method effectively separated the active drug from its degradation products, it can be employed as a stability-indicating assay method (SIAM) for identification and quantitative determination of duloxetine HCl in bulk drug and tablet dosage formulation.
Solubility is not the ability to dissolve or thaw a substance; it may happen not only due to dissolution but also because of a chemical reaction. Solubility is the phenomenon of dissolution of solid in liquid phase to provide a homogenous system. Solubility is one of the vital factors for accomplishing desired concentration of drug in systemic circulation for pharmacological response. Low aqueous solubility is the major problem seen with formulation development of new chemical entities as well as for the generic development. With all new discovered chemical entities about 40% drugs are lipophilic and doesn’t shown therapeutic range due to their poor water solubility. Drug with poor water solubility shows slow dissolution rates, incomplete absorption and low bioavailability when taken orally. Drug solubility and bioavailability enhancement are the important in the formulation of pharmaceuticals. The Biopharmaceutics Classification System shows that Class II and IV drugs have low water solubility, poor dissolution, and low bioavailability. This review mentions different approaches used for the enhancement of the solubility of poorly water-soluble drugs that includes particle size reduction, pH adjustment, and solid dispersion. This describes the techniques of solubilizaton for the attainment of effective absorption and improved bioavailability. Keywords: Solubility, BCS classification, Bioavailability, Solid-dispersion.
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