Ravi Mysore Shanker

Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried Dispersions: An Overview

Spray-dried dispersions (SDDs) of low-solubility drugs have been prepared using the polymer hydroxypropyl methylcellulose acetate succinate (HPMCAS). For a variety of drug structures, these SDDs provide supersaturation in in vitro dissolution determinations and large bioavailability increases in vivo. In bile-salt/lecithin in vitro solutions, these SDDs provide amorphous drug/polymer colloids and an increased concentration of free drug and drug in micelles relative to crystalline or amorphous drug. As dry powders, the SDDs are a single amorphous phase in which the drug remains amorphous and dispersed and does not crystallize over storage times relevant for practical drug products. A melting temperature (Tm)/glass-transition temperature (Tg) (K/K) versus log P map for 139 compounds formulated as SDDs provides a perspective on an appropriate formulation strategy for low-solubility drugs with various physical properties.

Solubility advantage of amorphous pharmaceuticals: I. A thermodynamic analysis

In recent years there has been growing interest in advancing amorphous pharmaceuticals as an approach for achieving adequate solubility. Due to difficulties in the experimental measurement of solubility, a reliable estimate of the solubility enhancement ratio of an amorphous form of a drug relative to its crystalline counterpart would be highly useful. We have developed a rigorous thermodynamic approach to estimate enhancement in solubility that can be achieved by conversion of a crystalline form to the amorphous form. We rigorously treat the three factors that contribute to differences in solubility between amorphous and crystalline forms. First, we calculate the free energy difference between amorphous and crystalline forms from thermal properties measured by modulated differential scanning calorimetry (MDSC). Secondly, since an amorphous solute can absorb significant amounts of water, which reduces its activity and solubility, a correction is made using water sorption isotherm data and the Gibbs-Duhem equation. Next, a correction is made for differences in the degree of ionization due to differences in solubilities of the two forms. Utilizing this approach the theoretically estimated solubility enhancement ratio of 7.0 for indomethacin (amorphous/gamma-crystal) was found to be in close agreement with the experimentally determined ratio of 4.9.

Glycogen phosphorylase inhibitor

Type 2 diabetes is a complex metabolic disease with hyperglycemia as its recognizable hallmark. Hepatic glucose output is elevated in Type 2 diabetic patients, and evidence suggests drugs which lower hepatic glucose production are effective antihyperglycemic agents. Glycogenolysis, which is the release of monomeric glucose from its polymeric storage form called glycogen, is a key contributor to hepatic glucose output. Glycogen phosphorylase is the enzyme that catalyzes this process. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes.

Solubility Advantage of Amorphous Pharmaceuticals: II. Application of Quantitative Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble Pharmaceuticals

ABSTRACTPurposeTo quantitatively assess the solubility advantage of amorphous forms of nine insoluble drugs with a wide range of physico-chemical properties utilizing a previously reported thermodynamic approach.MethodsThermal properties of amorphous and crystalline forms of drugs were measured using modulated differential calorimetry. Equilibrium moisture sorption uptake by amorphous drugs was measured by a gravimetric moisture sorption analyzer, and ionization constants were determined from the pH-solubility profiles. Solubilities of crystalline and amorphous forms of drugs were measured in de-ionized water at 25°C. Polarized microscopy was used to provide qualitative information about the crystallization of amorphous drug in solution during solubility measurement.ResultFor three out the nine compounds, the estimated solubility based on thermodynamic considerations was within two-fold of the experimental measurement. For one compound, estimated solubility enhancement was lower than experimental value, likely due to extensive ionization in solution and hence its sensitivity to error in pKa measurement. For the remaining five compounds, estimated solubility was about 4- to 53-fold higher than experimental results. In all cases where the theoretical solubility estimates were significantly higher, it was observed that the amorphous drug crystallized rapidly during the experimental determination of solubility, thus preventing an accurate experimental assessment of solubility advantage.ConclusionIt has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

Structural relaxation of acetaminophen glass.

PurposeThe aim is to determine the structural stability of acetaminophen glass with time and temperature change, and to examine the merits of adapting the structural relaxation models of the glassy state for pharmaceuticals.MethodsDifferential scanning calorimetry technique has been used to study the acetaminophen glass after keeping the samples for various periods at fixed temperatures and after keeping at various temperatures for fixed periods.ResultsA general formalism for thermodynamic changes during storage in a temperature fluctuating environment is given and the kinetics of the enthalpy and entropy decrease determined. At a fixed temperature, the decrease occurs according to a non-exponential kinetics. For the same storage time, but at different temperatures, the enthalpy and entropy decrease rises to a maximum value at a certain temperature and then declines. The peak appears at the temperature at which the internally equilibrated state of the sample is reached for a fixed storage time. The change in the normalized heat capacity during the heating of acetaminophen has been analysed in terms of a non-exponential, non-linear enthalpy relaxation model.ConclusionA single set of parameters that fit the data for unannealed acetaminophen glass does not fit the calorimetric data for annealed glass. Since acetaminophen molecules form intermolecular hydrogen-bonds in the crystal state and likely to form such bonds more easily in the disordered state, effect of such bonds on structural relaxation is likely to be significant.

Aqueous solubility of crystalline and amorphous drugs: Challenges in measurement

Measurement of drug solubility is one of the key elements of active pharmaceutical ingredient (API) characterization during the drug discovery and development process. This report is a critical review of experimental methods reported in the literature for the measurement of aqueous solubility of amorphous, partially crystalline and crystalline organic compounds. A summary of high-throughput automated methods used in early drug discovery research is also provided in this report. This review summarizes the challenges that are encountered during solubility measurement and the complexities that are often overlooked. Even though there is an advantage in using the amorphous form of a drug due to its higher solubility, measurement of its solubility with useful accuracy is still a practical problem. Therefore, this review provides recommendations of preferred methods and precautions in using these methods to determine the aqueous solubility of amorphous and crystalline new molecular entities, with emphasis on the physico-chemical characterization of the solid state of the test substance.

Dielectric Study of Equimolar Acetaminophen-Aspirin, Acetaminophen-Quinidine, and Benzoic Acid- Progesterone Molecular Alloys in the Glass and Ultraviscous States and Their Relevance to Solubility and Stability

Equimolar mixtures of acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T(g)s are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel-Fulcher-Tammann equation, log(10)(tau(0)) = A(VFT) + [B(VFT)/(T - T(0))], where A(VFT), B(VFT), and T(0) are empirical constants. The equilibrium permittivity is highest for the aspirin-acetaminophen and lowest for the benzoic acid-progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid-progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its alpha-relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery.

An in vitro technique for measuring contact angles on the corneal surface and its application to evaluate corneal wetting properties of water soluble polymers

Abstract The development of an in vitro technique capable of measuring the extent and duration of corneal wetting by demulcent polymers is reported. The technique required modification of a contact angle goniometer to facilitate the measurement of contact angles of demulcent polymer solutions on freshly enucleated rabbit eyes. Contact angles of the test solutions on the corneal surface was measured under physiologically relevant conditions. Contact angle measurements were performed under conditions to ensure that the tissue was not dehydrated and the native surface characteristics of the tissue were unchanged. Additionally, experimental procedures for contact angle measurements were developed in order to provide a partial simulation of in vivo fluid dynamics that is typically observed upon topical instillation of a drop of a test polymer solution into the eye of a patient. This multistep experimental procedure was initiated by briefly dipping a freshly enucleated rabbit eye in the test polymer solution. The treated eye was then immersed upside-down in an oxygenated, lactated Ringers solution and placed in the chamber of the goniometer. This medium was used to maintain ocular tissue viability and corneal surface integrity over the duration of the experiment. For measurement of contact angles, a well defined air bubble was slowly introduced into the chamber of the goniometer at close proximity to the enucleated eye. The air bubble was then entrapped on the corneal surface. Angle of contact of the air bubble against the corneal epithelial surface was visually measured with the goniometer. A new air bubble was entrapped at intervals of 5 min and the contact angle was measured as a function of time. The degree and duration of reduction of contact angle was observed to depend on the type and concentration of the water soluble polymer used. Most demulcents were found to rapidly desorb from the corneal surface. For these demulcent polymers the contact angle returned to pre-treatment values within 25 min of the start of the experiment. Hyaluronic acid showed the most sustained wetting of the cornea. The in vitro kinetic measurement of contact angle demonstrated the time dependent, marginally functional mucomimetic properties of demulcent polymers. The kinetics of desorption was considered to partially simulate the fluid dynamics in the eye. The validity of the inverted air bubble as well as this new technique for the kinetic measurement of contact angles was established on synthetic (polyethylene) surface prior to its utilization on freshly enucleated ocular surface. The measured contact angle and estimates of critical surface tension for polyethylene surface was in close agreement with values reported in the literature and with values obtained from conventional techniques of measurement of contact angle. The contact angle of lactated Ringers solution on the rabbit corneal surface range from 45 to 55°. Removal of mucin from the corneal surface increased the contact angle of the cornea in the range of 55–65°. This increase in contact angle of the corneal epithelium devoid of mucin indicated decreased wetting and demonstrated its greater hydrophobicity than the mucin coated epithelium. Adsorption of demulcent polymers solutions decreased the contact angles to as low as 30° indicating enhanced wetting of the cornea. The measurement of contact angles of various demulcent polymer solutions possessing different surface tensions made it possible to estimate the critical surface tension of the rabbit corneal epithelium. The critical surface tension, representing the minimal surface tension of a formulation necessary to completely wet and spread over the corneal epithelium was estimated at 39 dyn/cm. Therefore, the reported air bubble trapping along with the kinetic technique for measurement of contact angles may be useful as an in vitro screening tool for the evaluation of new demulcent polymers. The technique may also be used for the identification of superior tear substitutes for the treatment of dry eyes.