Dissolution testing for generic drugs: An FDA perspective

Dissolution testing has been evolved as an approach based on risk and science, to control the quality of pharmaceutical dosage forms, as well as to assist pharmaceutical product development, approval, and postapproval dossier submissions. It reduces regulatory burden, resource requirements, and thus development times and cost in the long, arduous, and expensive process of formulation development. It is considered as an important tool used in formulation development and optimization; estimation of drug release under physiological conditions; assurance of batch-to-batch consistency; stability monitoring; bioequivalence determination between pharmaceutical formulations. This chapter highlights the significance of the dissolution and the related concepts throughout the pharmaceutical drug development continuum. The initial part of the chapter outlines the development of a relevant dissolution test; taking into consideration all the parameters that influence its performance and results. The later part highlights the concepts of dissolution profile comparison, IVIVC and BCS (integrating with QbD), and their roles from nonclinical to the postmarketing stage of drug development to ensure a high-quality biopharmaceutical product of desirable attributes.

Dissolution Profile Consideration in Pharmaceutical Product Development

Fixed-dose combinations (FDCs) refer to products containing two or more active ingredients combined in a single dosage form. The FDCs are justified because of several advantages. These are a) poten...

A Critical Review on Analytical Methods for Recently Approved FDC Drugs: Pregabalin and Etoricoxib

Etoricoxib (EXB) is a highly selective cox-2 inhibitor which belongs to the non-steroidal anti-inflammatory drug (NSAID) EXB is a class II drug according to the biopharmaceutical classification system (BCS), which possess a very low aqueous solubility in water  In the present study, many trials were made to improve the aqueous solubility and dissolution rate of EXB by solid dispersion technique
Eighteenth EXB formulas were formulated as a solid dispersion using a variety of hydrophilic polymers (as carriers)   including poloxamer 407 (PXM 407), poloxamer 188 (PXM 188) and polyethylene glycol 4000 (PEG 4000) at different drug: polymer ratios (1:1, 1:3 and 1:5) These formulas were prepared by two methods; solvent evaporation and fusion method The prepared formulas were evaluated for practical yield percent (PY %), drug content, saturated solubility and release rate, Fourier transforms infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD)
It was found that the solubility was affected by the polymer type and the method of preparation The polymers (as carriers) used to prepare EXB- solid dispersion showed improvement in the solubility in the following descending order; PXM 407>PXM 188> PEG 4000 The optimum formula (SD15) composed of the drug: PXM 407 at a ratio of 1:5 was prepared by solvent evaporation showed 776 folds (67640%) solubility improvement as compared to pure EXB The optimum formula showed a release rate of 998% through the first 15 min The advance characterization of the selected formula indicated the possible transformation of the drug to the amorphous state
Keywords: EXB, Solid dispersion, PXM 407, PXM 188, PEG 4000

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Enhancement of Aqueous Solubility and Dissolution Rate of Etoricoxib by Solid Dispersion Technique

Lercanidipine hydrochloride (HCl) is L-type calcium channel blocker widely used in the management of hypertension. According to the BCS classification system, it is classified under BCS class II drugs, showing low solubility and high permeability. The dissolution profile and thus the in vivo performance of this class of drugs widely depend on their solubility and hence their behaviour in dissolution medium. Lercanidipine HCl is not official in any pharmacopeia, so no official dissolution method is available. The present work is mainly focussed on development and validation of a dissolution test that can be used as a quality control test for lercanidipine HCl tablets and formulations. Saturation solubility and sink conditions that can be achieved in different media suggested that 0.1 N HCl, acetate buffer pH 4.5, and phosphate buffer pH 6.8 can be used as a dissolution medium. Dissolution tests of lercanidipine HCl tablets were carried out in these different media at different rotation speeds using a USP type II (paddle) apparatus. The most suitable dissolution conditions were 0.1 N HCl pH 1.2 (900 mL at 37 ± 0.5 °C) as a dissolution medium and a paddle apparatus at 100 rpm for 60 min. The analysis of released lercanidipine HCl was done by ultraviolet spectrophotometry. The developed method was validated according to ICH guidelines. This method showed linearity with an r2 value of 0.999 within the concentration range of 2–20 μg/mL. The method was found to be accurate with recoveries ranging from 98.50% to 103.72%. The interday and intraday precision was below RSD 2%. The developed method can effectively be used for quality control evaluation of lercanidipine HCl tablets.

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Dissolution Method Development and Validation for Lercanidipine Hydrochloride Tablets

The availability of a discriminatory dissolution method for use in either quality control testing or product evaluation in quality by design trials is mandatory for products intended for the developed market. This study demonstrates the systematic development of a discriminatory dissolution method for etoricoxib, a BCS Class 2 drug exhibiting highly pH- dependent solubility. The pH, speed, and apparatus were simultaneously optimized and tested for method variability, reproducibility, and robustness. The discriminative power of the developed method was suitably demonstrated.

/pdf/discriminatory-dissolution-method-development-and-validation-4a6ln6uocy.pdf

Discriminatory Dissolution Method Development and Validation of Etoricoxib Tablets

Blending is a critical intermediate unit operation for all solid oral formulations. For blend uniformity testing, API content in the blend must be quantified precisely. A detailed study was conducted to demonstrate the suitability of inline NIR (near-infrared) spectroscopy for blend uniformity testing of two solid oral formulations: existing direct compression (DC) product with a multistep blending process and granulation-based product with API granules. Both qualitative and quantitative methods were developed at a laboratory scale using statistical moving block standard deviation (MBSD) and multivariate data analysis such as principal component analysis (PCA) and partial least squares (PLS) regression. The qualitative MBSD method demonstrated that there was no need for multiple steps for the existing DC product. Hence, a simplified single-step process was developed for blending. Quantitative PLS models for blending processes of both the products were developed, validated, and successfully implemented at a commercial scale for the real-time release of blends. Results obtained from the validated model were in good agreement with the current method of sampling and chromatography.

Development of Inline Near-Infrared Spectroscopy Method for Real-Time Monitoring of Blend Uniformity of Direct Compression and Granulation-Based Products at Commercial Scales

Abstract Near Infrared and Raman spectroscopy-based Process Analytical Technology tools were used for monitoring blend uniformity (BU) and content uniformity (CU) for solid oral formulations. A quantitative Partial Least Square model was developed to monitor BU as real-time release testing at a commercial scale. The model having the R 2, and root mean square error of 0.9724 and 2.2047, respectively can predict the target concentration of 100% with a 95% confidence interval of 101.85–102.68% even after one year. The tablets from the same blends were investigated for CU using NIR and Raman techniques both in reflection and transmission mode. Raman reflection technique was found to be the best and the PLS model was developed using tablets compressed at different concentrations, hardness, and speed. The model with R 2 and RMSE of 0.9766 and 1.9259, respectively was used for the quantification of CU. Both the BU and CU models were validated for accuracy, precision, specificity, linearity, and robustness. The accuracy was proved against the HPLC method with a relative standard deviation of less than 3%. The equivalency for BU by NIR and CU by Raman was evaluated using Schuirmann’s Two One-sided tests and found equivalent to HPLC within a 2% acceptable limit. Graphical Abstract

Towards a real-time release of blends and tablets using NIR and Raman spectroscopy at commercial scales

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Discriminatory Dissolution Method Development and Validation of Etoricoxib Tablets

Development of Inline Near-Infrared Spectroscopy Method for Real-Time Monitoring of Blend Uniformity of Direct Compression and Granulation-Based Products at Commercial Scales

Towards a real-time release of blends and tablets using NIR and Raman spectroscopy at commercial scales