Naveen K. 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.

The quest for targeted delivery in colon cancer: mucoadhesive valdecoxib microspheres.

The aim of the present study was to prepare valdecoxib, a cyclo-oxygenase-2 enzyme inhibitor, as a loaded multiparticulate system to achieve site-specific drug delivery to colorectal tumors. Film coating was done with the pH-sensitive polymer Eudragit S100 and sodium alginate was used as mucoadhesive polymer in the core. The microspheres were characterized by X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy and were evaluated for particle size, drug load, in vitro drug release, release kinetics, accelerated stability, and extent of mucoadhesion. The coated microspheres released the drug at pH 7.4, the putative parameter for colonic delivery. When applied to the mucosal surface of freshly excised goat colon, microspheres pretreated with phosphate buffer pH 7.4 for 30 minutes showed mucoadhesion. To ascertain the effect of valdecoxib on the viability of Caco-2 cells, the 3-(4,5-dimethylthiazol-2yl) 2,5-diphenyltetrazolium bromide) test was conducted using both valdecoxib and coated microspheres. In both cases, the percentage of dehydrogenase activity indicated a lack of toxicity against Caco-2 cells in the tested concentration range. Drug transport studies of the drug as well as the coated microspheres in buffers of pH 6 and 7.4 across Caco-2 cell monolayers were conducted. The microspheres were found to exhibit slower and delayed drug release and lower intracellular concentration of valdecoxib.

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.

Compression-induced polymorphic transformation in tablets: Role of shear stress and development of mitigation strategies

Our goals were to evaluate the effects of (i) hydrostatic pressure alone and (ii) its combined effect with shear stress during compaction, on the polymorphic transformation (form C → A) of a model drug, chlorpropamide. The powder was either subjected to hydrostatic pressure in a pressure vessel or compressed in a tablet press, at pressures ranging from 25 to 150 MPa. The overall extent of phase transformation was determined by powder X-ray diffractometry, whereas 2D-X-ray diffractometry enabled quantification of the spatial distribution of phase composition in tablets. Irrespective of the pressure, the extent of transformation following compaction was higher than that because of hydrostatic pressure alone, the difference attributed to the contribution of shear stress experienced during compaction. At a compression pressure of 25 MPa, there was a pronounced gradient in the extent of phase transformation when monitored from radial tablet surface to core. This gradient decreased with increase in compression pressure. Four approaches were attempted to minimize the effect of compression-induced phase transformation: (a) site-specific lubrication, (b) use of a viscoelastic excipient, (c) ceramic-lined die, and (d) use of cavity tablet. The ceramic-lined die coupled with site-specific lubrication was most effective in minimizing the extent of compression-induced phase transformation.