Development of near infrared spectroscopic methods to predict and understand dissolution of solid oral dosage forms

Abstract

Shear stress is created in a system by moving one surface over another to cause displacements in the direction of the moving surface. Shearing of powder is essential to break down agglomerates in cohesive powders, promoting micro-mixing, and thus uniform blends. During material processing, particles rub against each other, leading to development of shear forces. In solid dosage manufacturing, powder is subjected to different unit operations, and thus to different levels of normal and abrasive stresses and strain. This mechanical shear also affects the hydrophobicity of pharmaceutical powder blends and its impact on drug release from tablets during dissolution testing.

The dissolution test is required in the development, registration, approval and quality control of a solid oral dosage form except where the label says that they are to be chewed. The dissolution test is required by over 500 tablet and capsule products described in the United States Pharmacopeia (USP), and is the only test performed in manufacturing with the objective of monitoring whether the product will perform adequately throughout its shelf life.

Drug concentration in the dissolution medium is currently determined with High Performance Liquid Chromatography (HPLC) or Ultraviolet/Visible Spectroscopy (UV/VIS) using solvents with high cost and leading to significant solvent wastes generated in the analysis. USP establishes in chapter <711> four different systems to perform dissolution test. USP Apparatus 1 (Basket) and 2 (Paddle) consist in a fixed volume of dissolution medium. USP apparatus 3 (Reciprocating Cylinder) and 4 (Flow-Through Cell) when the USP Apparatus 1 and 2 are not suitable for the analysis (e.g. polymeric thin films). This type of testing destroys the tablets leaving nothing to investigate if the test fails. Based on that information, a nondestructive method for dissolution analysis of tablets id needed. Near infrared spectroscopy is a non-destructive fast technique suitable for these purposes. NIR is an analytical method capable of monitoring critical quality parameters that are valuable in the improvement of pharmaceutical processes. Near infrared spectroscopy has become one of the most used analytical techniques to monitor pharmaceutical processes since the spectra provides information on the physical and chemical properties, and can obtain a high signal to noise ratio spectrum in one minute without sample preparation.

This dissertation describes three studies to enhance the understanding of near infrared spectroscopy and chemometrics and to advance their adoption within pharmaceutical manufacturing. The first study was based on the changes observed in the near infrared diffuse reflectance spectra of pharmaceutical tablets after these tablets were subjected to different levels of strain (exposure to shear) during the mixing process. These changes in the near infrared spectra (NIR) could affect results obtained from NIR calibration models. Shear was applied using a Couette cell and tablets were produced using a tablet press emulator. Tablets with different shear levels were measured using near infrared spectroscopy in the diffuse reflectance mode. The NIR spectra were baseline corrected to maintain the scattering effect associated with the physical properties of the tablet surface. Principal Component Analysis was used to establish the principal sources of variation within the samples. The angular dependence of elastic light scattering shows that the shear treatment reduces the size of particles and produces their uniform and highly isotropic distribution. Tablet compaction further reduces the diffuse component of scattering due to realignment of particles. The aim of the study was to understand changes in the near infrared diffuse reflectance spectra that can be associated with different levels of shear developed during blend shearing of laboratory samples.

A second study describes how the shear applied to the formulation affects the dissolution, and how near infrared spectroscopy can be used to predict dissolution. This stress affects the dissolution of oral solid dosages forms. However, dissolution testing destroys the entire tablet, making it impossible to evaluate tablet properties when an out of specification result is obtained. Thus, a nondestructive technique such as near infrared spectroscopy is desirable to predict dissolution. The aim of this study was to predict dissolution on tablets with different levels of shear using near infrared spectroscopy in combination with multivariate data analysis. Dissolution profiles were obtained using United States Pharmacopeia (USP) Apparatus 2 as a reference method. Principal component analysis was used to study the sources of variation in the spectra obtained. Partial least squares 2 was used to predict dissolution on tablets with different levels of shear.

The third set of studies consisted in two collaborative studies using near infrared chemical imaging (NIRCI). The first study consisted in the investigation of Active Pharmaceutical Ingredient (API) distribution in a pharmaceutical blend using a Resonant Acoustic Mixer. The resonant acoustic mixer promotes macro and micromixing without providing mechanical force to the blend. the qualitative and quantitative results correlates the acceleration force and total mixing time with aggregate surface are on the samples. Overall, the resonant acoustic mixing performance increased with increasing acceleration force and mixing time promoting agglomeration of the API on the samples.

The use NIRCI was also investigated to evaluate the possible correlation between the variability of gelatin and chitosan with his mechanical properties of the edible films. Edible films are used in the food industry to extend the shelf life of products. Near infrared chemical Imaging was used to determine the abundance of films containing Chitosan and gelatin with different combination of plasticizer. The chemical images were obtained, and preprocess with standard normal variate and second derivative to enhance the signal of chitosan and gelatin on the films. Abundance results shows proper distribution of chitosan and gelatin on films with different plasticizers. Statistical results shows a correlation between the abundance and the tensile strength of the films.