Opportunities and Challenges: Process Raman for the Real-Time Release Testing (RTRT) of Extended-Release Formulations

Abstract

The use of a process analytical technology has been demonstrated using near-infrared spectroscopy for continuous manufacturing of pharmaceutical formulations and is within the scope of the U.S. Food and Drug Administration‘s real-time release testing initiative. While effective for simple formulations, this preliminary study investigates whether such a spectroscopic surrogate application can replace pharmaceutical dissolution testing for extended-release formulations. In this study, we will assess the use of process Raman spectroscopy for real-time dissolution testing. Extended-release tablet formulations often accomplish the release rate delay through the addition of gelling agents.

In this work, hydroxypropyl methylcellulose (HPMC) polymers were used to formulate extended-release niacin tablets. Process Raman spectroscopy was evaluated as a tool to effectively model dissolution profiles to determine if the optical technique has the ability to differentiate HPMC polymers from the background and be selective for the polymer type employed. Our preliminary work indicates that while Raman can effectively detect and monitor the niacin response of the tablet formulations, there are not enough unique spectral features between the different HPMC polymers to selectively resolve their responses. Additional measurements and chemometric analysis might suggest otherwise. Thus, for extended-release tablet applications with continuous manufacturing, further dissolution surrogate development is needed.

Introduction

In an attempt to lower manufacturing costs and improve efficiency, the pharmaceutical industry is moving to wider applications of continuous manufacturing and rapid-release testing.This rapid testing has successfully modeled dissolution testing for continuous manufacturing applications for simple formulations. The Food and Drug Administration recognizes this capability and cites examples of real-time release testing (RTRT), which includes “multivariate analysis models as a surrogate for dissolution.”Use of such models is not as simple as submitting a traditional method and validation. Submission of such a model would require (i) a full description of data collection, pretreatment, and analysis, (ii) justification of the model building approach, (iii) statistical summary of results, (iv) verification using data external to the calibration set, and (v) a discussion of approaches to model maintenance and updates.

Raman spectroscopy, a vibrational spectroscopic technique is a process analytical technology (PAT) that is quickly being implemented and deployed in the pharmaceutical manufacturing and testing process. The technique is attractive primarily due to the rich, real-time compositional data generated, the ease of implementing it in a process, and the minimal response to water. Raman spectroscopy has been used as an in-line PAT tool with continuous manufacturing testing and traditional pharmaceutical dissolution testing.There are other PAT spectroscopic tools that have also been used for dissolution applications but due to the transparency to water, Raman spectroscopy has become the tool of choice. This investigation is the first in the literature to apply Raman spectroscopy for rapid-release dissolution modeling of extended-release tablets.

A representative extended-release matrix was chosen for evaluation. Successful implementation of this capability would directly impact many products both in development and in the market. Typically, tablet manufacture of extended-release formulations requires critical parameter controls to be set up within a dissolution design space. To model the extended-release capability of the formulation, and thus the resulting dissolution profile, the spectroscopic technique employed must be able to reliably detect the release profile change from each formulation design. Thus, if a Raman library could distinguish between, dissolution release changes due to hardness, lubricants, particle sizes, etc., the spectroscopic tool could serve as a surrogate for lengthy dissolution testing similar to the earlier work using near-infrared for continuous manufacturing. Such modeling would require a much larger body of data for the spectral library.

The challenge is that dissolution studies for extended-release matrices often take several hours to execute. The application and transfer of methods using USP Apparatus I and II, Apparatus III, and Apparatus IV2 could be replaced with rapid spectroscopic evaluation models that require only a few minutes. In addition, all samples going to the clinic could be effectively modeled. Once the dissolution model was determined the Raman model could also potentially yield drug potency and content uniformity,27 as well as crystallinity determination for enabling amorphous formulations. The notion of using Raman spectroscopy in this regard is appealing for an extended-release formulation. Perhaps, Raman spectroscopy could be the missing tool for in vivo/in vitro correlations for the pharmaceutical industry.

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Materials

Niacin used in this investigation was ≥98% from Sigma. All excipients were commercial grade from warehouse vendors. Hydroxypropyl methylcellulose (HPMC) polymers Methocel K100LV and K15M were used as received from Dow. Mannitol was Pearlitol 100 SD grade from Roquette. Microcrystalline Cellulose was Avicel PH 102 grade from FMC Biopolymer. Colloidal silicon dioxide was from Cabot Corporation and the magnesium stearate used was compendial grade from Mallinckrodt Pharmaceuticals. Standard industry practices were used to control particle uniformity in the raw materials.

Webster GK, Mankani B, Mozharov S, Marquardt B. Opportunities and Challenges: Process Raman for the Real-Time Release Testing (RTRT) of Extended-Release Formulations. Applied Spectroscopy Practica. 2024;2(2). doi:10.1177/27551857241248477