Structure, Solubility and Stability of Orbifloxacin Crystal Forms: Hemihydrate versus Anhydrate.

Orbifloxacin (ORBI) is a widely used antimicrobial drug of the fluoroquinolone class. In the official pharmaceutical compendia the existence of polymorphism in this active pharmaceutical ingredient (API) is reported. No crystal structure has been reported for this API and as described in the literature, its solubility is very controversial. Considering that different solid forms of the same API may have different physicochemical properties, these different solubilities may have resulted from analyses inadvertently carried out on different polymorphs. The solubility is the most critical property because it can affect the bioavailability and may compromise the quality of a drug product. The crystalline structure of ORBI determined by SCXRD is reported here for the first time. The structural analysis reveals that the ORBI molecule is zwitterionic and hemihydrated. ORBI hemihydrated form was characterized by the following techniques: TG/DTA, FTIR-ATR, and PXRD. A second crystalline ORBI form is also reported: the ORBI anhydrous form was obtained by heating the hemihydrate. These ORBI solid forms were isomorphous, since no significant change in unit cell and space group symmetry were observed. The solid-state phase transformation between these forms is discussed and the equilibrium solubility data were examined in order to check the impact of the differences observed in their crystalline structures.

A New Crystalline Ketoprofen Sodium Salt: Solid-State Characterization, Solubility, and Stability.

Ketoprofen (KTP) is an Active Pharmaceutical Ingredient (API) that has low solubility in aqueous solvents. The use of KTP salts has attracted attention due to its improvements in terms of solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a crystalline KTP sodium salt (coded as KTP-Na) was successfully obtained and widely characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), solubility and accelerated stability studies. XRD results showed that KTP-Na is not yet reported in the literature. Moreover, FTIR, DSC and TGA were useful for differentiation of KTP-Na from the KTP commercialized form (coded as KTP-R1). The solubility of KTP-Na in water was about 80 times greater than the KTP-R1. However, KTP-Na showed lower physical stability in storage conditions at 40 ± 2°C/ 75% ± 5% RH when compared to KTP-R1, which was shown to be related to a high hygroscopicity of KTP-Na. Therefore, due to its higher solubility, KTP-Na may be a viable alternative for use in solid dosage forms. However, the presence of moisture must be strictly controlled to avoid water absorption and consequent amorphization.

A review of analytical techniques for determination of glimepiride: present and perspectives.

Glimepiride is an oral antidiabetic drug in the sulfonylurea class, which is widely used in treatment of Type 2 diabetes and it is currently available in more than 60 countries worldwide. As a result of the importance of this oral hypoglycemic agent in the treatment of noninsulin-dependent diabetes mellitus, this work aims to compile the published analytical methods reported so far in the literature for determination of glimepiride in biologic samples and pharmaceutical formulations. Techniques like high-performance liquid chromatography with ultraviolet, array-diode, mass spectroscopy, evaporative light scattering and charged aerosol detections, liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry, liquid chromatography-electrospray ionization-tandem mass spectrometry, semimicrobore high-performance liquid chromatography with column-switching, micellar electrokinetic chromatography, high-performance thin layer chromatography, polarography, and spectrophotometry have been used for analysis, from which it can be seen that high-performance liquid chromatography methods have been used most extensively.

A Critical Review of Analytical Methods in Pharmaceutical Matrices for Determination of Corticosteroids.

Corticosteroids are a class of hormones released by the adrenal cortex, which includes glucocorticoids and mineralocorticoids. Glucocorticoids have an important role in the metabolism of carbohydrates, proteins and calcium and effective anti-inflammatory and immunosuppressive activity. Due to their intense immunomodulatory and anti-inflammatory activity, glucocorticoids are used in the treatment of various inflammatory, malignant, allergic conditions such as rhinitis, asthma, dermatological, rheumatic, ophthalmic and neurological diseases, as well as after organ transplants. They are the most widely prescribed drugs in the world. The objective of this review is to provide an overview of the analytical methods in pharmaceutical matrices for determination of corticosteroids. In this study, the predominance of liquid chromatography methods for the analysis of corticosteroids from pharmaceutical products is evident for both liquid and semisolid dosage forms as well as for solids. The same can be said for topical, oral and parenteral formulations. Methods such as spectrophotometry are also used, but given the advantages of chromatographic methods such as better selectivity and sensitivity, they have become the choice for analysis of these drugs, however, most methods still do not meet the credentials of "green chemistry."

Analytical Methods for the Determination of Rosuvastatin in Pharmaceutical Formulations and Biological Fluids: A Critical Review.

Rosuvastatin calcium (ROS), ( Figure 1 ) belongs to the "statins" group, which is the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. This drug is indicated for dyslipidemias treatment and can help to decrease the level of "bad cholesterol" and can consequently reduce the development of atherosclerosis and the risk of heart diseases. ROS was developed by Astra-Zeneca and it was approved in 2003 by the FDA in the United States. In 2015, under the trade name Crestor®, it was the fourth largest selling drug in the United States with sales above $5 billion. This study presents a literature review of analytical methods for the quantification of ROS in pharmaceutical preparations and biological fluids. The major analytical methods described in this study for ROS were spectrophotometry, high-performance liquid chromatography (HPLC) coupled to ultraviolet (UV) detection, and tandem mass spectrometry (LC-MS/MS).

Pharmacokinetics and pharmacodynamics of glimepiride polymorphs.

Glimepiride (GLIM) is used as an oral antihyperglycemic agent for treatment of type 2 diabetes. The drug presents two polymorphic forms (GLIM form I and GLIM form II) described in the literature, and according to in vitro data, GLIM form II is about 3.5 times more soluble and releases 2 times the drug amount than GLIM form I in the physiological pH range. Considering the literature in vitro data and that the diabetes treatment demands glycemic control, avoiding abrupt fluctuations in the blood glucose levels, this work aimed to study the impact of GLIM polymorphism in the in vivo performance of GLIM solid oral dosages. For this, hard gelatin capsules with GLIM form I or II were prepared and orally administered in rats. After that, pharmacokinetic studies were performed by sampling animal blood at different times, and biochemical parameters (pharmacodynamic), such as glucose and insulin, were also evaluated. Our results showed that the in vitro data corroborate with our in vivo assays. GLIM form II provided higher plasma concentration of drug than form I (at baseline up to approximately 200 min after oral administration) and, consequently, increased insulin release and reduced levels of glucose, showing good correlation between pharmacokinetic and pharmacodynamics assays. Thus, this study demonstrated that GLIM polymorphs in oral dosages might alter the drug efficacy, which may expose the patients to risks, such as hypoglycemia.

Analysis of polymorphic contamination in meloxicam raw materials and its effects on the physicochemical quality of drug product.

This work aims to evaluate the effect of polymorphism on the physicochemical properties of meloxicam, which is an antipyretic and non-steroidal anti-inflammatory drug. Powder X-ray Diffraction, Infrared Spectroscopy with attenuated total reflectance, Thermogravimetric and Differential Scanning Calorimetry techniques were used for the polymorphic characterization. Comparative tests of solubility, intrinsic dissolution and dissolution profiles were performed on meloxicam active pharmaceutical ingredients (APIs) and formulated tablets. A polymorphic contamination (Forms I and III) was found in a studied meloxicam batch, which showed a higher solubility and greater intrinsic dissolution than those containing only the preconized form (Form I). Consequently, the dissolution profiles of the tablets that contained the polymorphic contamination showed higher drug release. Additionally, a thermal behavior study shows that MLX Form I and III are monotropy polymorphs being MLX Form III a metastable phase, which becomes MLX Form I at approximately 200°C in solid state phase transition governed by kinetic variables. The kinetic of conversion of Form III to Form I in saturated solutions was also studied. These results illustrate the importance of the polymorphic characterization of meloxicam APIs and formulated tablets in order to avoid potential quality and efficacy problems of drug products.

Molecularly imprinted microparticles in lipid-based formulations for sustained release of donepezil.

Donepezil is a drug administered for Alzheimer's disease treatment, and it is a potential template molecule for imprinted microparticles. The precipitation polymerization technique allows the synthesis of spherical imprinted microparticles, and the intermolecular interactions among drug and molecularly imprinted polymers (MIPs) play a promising role for delineating drug delivery systems. Once that donepezil is a poorly-water soluble compound, lipid based-formulations (LBFs) may enhance its oral administration. Based on this, LBFs are useful vehicles to incorporate imprinted microparticles synthesized by precipitation polymerization. In these formulations, the drug dissolved in lipids is accessible to adsorbate in the polymers, and the hydrophobic environment of lipids increases the molecular recognition of MIPs. The formulations based on MIPs using pure oleic acid as vehicle prolong the in vitro release of donepezil up to several hours by a Fickian diffusion mechanism, and it provides a multiphasic release pattern related to the heterogeneity of the binding sites. The modulation of donepezil release from MIPs-based formulations using oil vehicles may contribute to decrease its side effects, possibly regulating its absorption rate in the gastrointestinal tract. These systems represent a novel technological platform to prolong the delivery not only for donepezil, but also for a variety of therapeutics.

Multivariate optimization and validation of an analytical methodology by RP-HPLC for the determination of losartan potassium in capsules.

This paper describes the optimization and validation of an analytical methodology for the determination of losartan potassium in capsules by HPLC using 2(5-1) fractional factorial and Doehlert designs. This multivariate approach allows a considerable improvement in chromatographic performance using fewer experiments, without additional cost for columns or other equipment. The HPLC method utilized potassium phosphate buffer (pH 6.2; 58 mmol L(-1))-acetonitrile (65:35, v/v) as the mobile phase, pumped at a flow rate of 1.0 mL min(-1). An octylsilane column (100 mm x 4.6mm i.d., 5 microm) maintained at 35 degrees C was used as the stationary phase. UV detection was performed at 254 nm. The method was validated according to the ICH guidelines, showing accuracy, precision (intra-day relative standard deviation (R.S.D.) and inter-day R.S.D values <2.0%), selectivity, robustness and linearity (r=0.9998) over a concentration range from 30 to 70 mg L(-1) of losartan potassium. The limits of detection and quantification were 0.114 and 0.420 mg L(-1), respectively. The validated method may be used to quantify losartan potassium in capsules and to determine the stability of this drug.