Seema Thakral

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives. Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed. Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.

Prediction of Drug–Polymer Miscibility through the use of Solubility Parameter based Flory–Huggins Interaction Parameter and the Experimental Validation: PEG as Model Polymer

Important consideration for developing physically stable solid dispersion is miscibility of drug in carrier matrix. It is possible to predict thermodynamics of binary system through free energy calculations based on Flory-Huggins interaction parameter (χ(dp)). In present study, PEG 6000 as model polymer and dataset comprising commonly used drugs/excipients was selected. The three-dimensional solubility parameter based on group contribution method was utilized for systemic calculation of χ(dp) of the polymer with each compound in data set. On the basis of the values of χ(dp), it was possible to categorize all the compounds into three distinct categories, Types I and II: compounds predicted to be miscible and immiscible respectively with the polymer in all proportions and Type III: compounds expected to exhibit composition dependent miscibility behavior. The Bagley plot showed that majority of points for Type I fall in a region, which can approximately be delimited by a circle. Experimental verification through thermal analysis revealed that though it was possible to predict correctly miscibility behavior of Type II class compounds, distinction between Types I and III was less evident. Hence, solubility parameter based χ(dp) may be used as an initial tool for fast screening of immiscible combination of polymer and drug.

Fullerenes: An introduction and overview of their biological properties

Ever since their experimental discovery in 1985, fullerenes have attracted considerable attention in different fields of sciences. Investigations of chemical, physical and biological properties of fullerenes have yielded promising information. Their unique carbon cage structure coupled with immense scope for derivatization makes fullerenes a potential therapeutic agent. Henceforth various potential therapeutic applications of fullerenes have been reviewed in the present paper. These include antiHIV- protease activity, photodynamic DNA cleavage, free radical scavenger, antimicrobial action and use of fullerenes as diagnostic agents.

Instability in Theophylline and Carbamazepine Hydrate Tablets: Cocrystal Formation Due to Release of Lattice Water

PurposeTo demonstrate two sequential solid-state reactions in intact tablets: dehydration of active pharmaceutical ingredient (API), and cocrystal formation between the anhydrous API and a second formulation component mediated by the released water. To evaluate the implication of this in situ phase transformation on the tablet dissolution behavior.MethodsTablets containing theophylline monohydrate (TPM) and anhydrous citric acid (CA) were stored at 40°C in sealed polyester pouches and the relative humidity in the headspace above the tablet was continuously measured. Dehydration to anhydrous theophylline (TPA) and the product appearance (TPA-CA cocrystal) were simultaneously monitored by powder X-ray diffractometry. Carbamazepine dihydrate and nicotinamide formed the second model system.ResultsThe water of crystallization released by TPM dehydration was followed first by deliquescence of citric acid, evident from the headspace relative humidity (~ 68%; 40°C), and then the formation of TPA-CA cocrystal in intact tablets. The noncovalent synthesis resulted in a pronounced decrease in the dissolution rate of theophylline from the tablets. Similarly, the water released by dehydration of carbamazepine dihydrate caused the cocrystallization reaction between anhydrous carbamazepine and nicotinamide.ConclusionsThe water released by API dehydration mediated cocrystal formation in intact tablets and affected dissolution behavior.

Urea inclusion compounds of enalapril maleate for the improvement of pharmaceutical characteristics

Urea is a well known adductor for linear organic compounds. In the present study, enalapril maleate, a substituted cyclic organic compound, was successfully included in urea together with a suitable rapidly adductible endocyte (RAE). Formation of the urea inclusion compound was confirmed by Fourier transform infrared spectroscopy, differential scanning calorimetry and X‐ray diffraction. The modified Zimmerschied calorimetric method was used to estimate the minimum amount of RAE required for adduction of enalapril maleate in urea. Urea‐enalapril maleate‐RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behaviour studied by differential scanning calorimetry. Regression analysis revealed an excellent r2 value with regard to the influence of the relative proportion of RAE on the heat of decomposition. The inclusion compounds were found to exhibit good content uniformity and improved dissolution profile as demonstrated by increased dissolution efficiency. Studies revealed that urea inclusion may be a promising alternative for the formulation of potent poorly soluble drugs into immediate release products.

Construction and Validation of Binary Phase Diagram for Amorphous Solid Dispersion Using Flory–Huggins Theory

Drug–polymer miscibility is one of the fundamental prerequisite for the successful design and development of amorphous solid dispersion formulation. The purpose of the present work is to provide an example of the theoretical estimation of drug–polymer miscibility and solubility on the basis of Flory–Huggins (F–H) theory and experimental validation of the phase diagram. The F–H interaction parameter, χd-p, of model system, aceclofenac and Soluplus, was estimated by two methods: by melting point depression of drug in presence of different polymer fractions and by Hildebrand and Scott solubility parameter calculations. The simplified relationship between the F–H interaction parameter and temperature was established. This enabled us to generate free energy of mixing (ΔGmix) curves for varying drug–polymer compositions at different temperatures and finally the spinodal curve. The predicted behavior of the binary system was evaluated through X-ray diffraction, differential scanning calorimetry, and in vitro dissolution studies. The results suggest possibility of employing interaction parameter as preliminary tool for the estimation of drug–polymer miscibility.

Urea co‐inclusion compounds of 13 cis‐retinoic acid for simultaneous improvement of dissolution profile, photostability and safe handling characteristics

13‐cis Retinoic acid (cis‐RA), a synthetic retinoid used in the treatment of severe acne, is known to exhibit extremely low aqueous solubility and high photosensitivity. In this study, urea, a well‐known adductor for linear compounds, was successfully employed for the adduction of cis‐RA — a substituted cyclic organic compound. Formation of urea inclusion compounds was confirmed by FTIR, DSC and XRD. A modified Zimmerschied calorimetric method was employed for the estimation of the minimum amount of rapidly adductible endocyte (RAE) required for adduction of cis‐RA in urea. Urea–cis‐RA‐RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behaviour studied by DSC. The inclusion compounds were found to have an improved dissolution profile as demonstrated by an overall increase in the dissolution efficiency. An accelerated photostability study, conducted as per Q1B ICH guidelines, revealed that co‐inclusion of cis‐RA in urea delayed photo‐degradation of the drug when compared with that of the pure drug. The results suggest the possibility of exploiting co‐inclusion of the drug in a urea host lattice for improved solubility, stability and reduced handling problems for cis‐RA.

Reduction in Moisture Sensitivity/Uptake of Moisture Sensitive Drugs Through Adduction in Urea

In the present study, use of hexagonal urea as a means for the reduction in moisture sensitivity/uptake has been investigated using nicorandil as a model endocytic drug. Urea, a well-known adductor for linear compounds, was successfully employed for adduction of nicorandil—a substituted cyclic organic compound through recently reported technique. Formation of urea inclusion compounds was confirmed by Fourier transform infrared, differential scanning calorimetry (DSC) and X-ray diffraction. Modified Zimmerschied calorimetric method was employed for estimation of the minimum amount of rapidly adductible endocyte (RAE) required per unit weight of nicorandil for adduction in urea. Urea–nicorandil–RAE inclusion compounds containing varying proportions of guests were prepared and their thermal behavior studied by DSC. However, coinclusion of nicorandil—a normally non-adductible endocytic compound in urea—naturally resulted in distortion of narrow channels of hexagonal lattice leading to the formation of distorted hexagonal urea. Both the normal and distorted hexagonal urea revealed appreciable reduction in moisture uptake when compared to that of tetragonal urea. The distorted urea framework exhibited increased moisture uptake as compared to the non-distorted one. Study also revealed improved stability of included nicorandil upon exposure to atmosphere at higher humidity levels. The coinclusion compounds of nicorandil were found to exhibit good content uniformity. Urea inclusion compounds of nicorandil in the presence of suitable RAE can be a promising alternative for the development of stable formulations of the drug.

Development and in vivo evaluation of a novel lyophilized formulation for the treatment of hemorrhagic shock

Hemorrhagic shock, caused by trauma, is a leading cause of preventable death. A combination treatment of d-β-hydroxybutyrate (BHB) and melatonin (MLT), in dimethyl sulfoxide - water, increased survival. A freeze-dried BHB-MLT formulation, with a short reconstitution time, has been developed. This intravenous formulation, prepared with an aqueous vehicle, completely eliminated dimethyl sulfoxide, thereby avoiding the potential problems associated with this solvent. The poor aqueous solubility of MLT necessitated the use of polyvinylpyrrolidine (PVP) as a complexing agent. Thus the prelyophilization solution contained BHB (2 M), MLT (21.5 mM) and PVP (40 mM). Using a combination of low-temperature X-ray diffractometry and thermal analysis, the lyophilization process parameters were optimized. Infra-red spectra revealed hydrogen bonding interaction between PVP and MLT, while BHB crystallized as BHB.0.25 H2O in the final lyophile. The formulation improved survival in a rat model of hemorrhagic shock. Based on the increase in rate of survival and longer survival time compared to untreated animals, we conclude that this formulation can serve as a promising first line of treatment for hemorrhagic shock.

Estimation of Drug Particle Size in Intact Tablets by 2-Dimensional X-Ray Diffractometry

The average grain size of a crystalline material can be determined from the γ-profile of Debye rings in 2-dimensional X-ray diffraction frames. Our objectives were to: (1) validate the method for organic powders and use it to determine the grain size in intact tablets, and (2) demonstrate the pharmaceutical application of this technique by determining the grain size of the active pharmaceutical ingredient in marketed formulations. Six sieve fractions of sucrose were prepared and the particle size distribution was confirmed by laser diffraction. Their average grain size was determined from the 2-dimensional X-ray diffraction frames by the γ-profile method. For particles <90 μm (based on sieving), the average particle size determined by the 3 methods were in good agreement. When these particles were compressed, there was no discernible change in the sucrose grain size in tablets. When the particles were >250 μm, compression resulted in a mixture of large grains and fine powder. The grain size of acetaminophen in 11 marketed tablet formulations was determined to be either ∼35 μm or ∼80 μm. This nondestructive technique can therefore be potentially useful to estimate the grain size of crystalline formulation components in intact tablets.