Integrative Salt Selection and Formulation Optimization: Perspectives of Disproportionation and Microenvironmental pH Modulation.

We report a novel utilization of a pH modifier as a disproportionation retardant in a tablet formulation. The drug molecule of interest has significant bioavailability challenges that require solubility enhancement. In addition to limited salt/cocrystal options, disproportionation of the potential salt(s) was identified as a substantial risk. Using a combination of Raman spectroscopy with chemometrics and quantitative X-ray diffraction in specially designed stress testing, we investigated the disproportionation phenomena. The learnings and insight drawn from crystallography drove the selection of the maleate form as the target API. Inspired by the fumarate form's unique stability and solubility characteristics, we used fumaric acid as the microenvironmental pH modulator. Proof-of-concept experiments with high-risk (HCl) and moderate-risk (maleate) scenarios confirmed the synergistic advantage of fumaric acid, which interacts with the freebase released by disproportionation to form a more soluble species. The resultant hemifumarate helps maintain the solubility at an elevated level. This work demonstrates an innovative technique to mediate the solubility drop during the "parachute" phase of drug absorption using compendial excipients, and this approach can potentially serve as an effective risk-mitigating strategy for salt disproportionation.

Pharmaceutical Forced Degradation (Stress Testing) Endpoints: A Scientific Rationale and Industry Perspective.

Forced degradation (i.e., stress testing) of small molecule drug substances and products is a critical part of the drug development process, providing insight into the intrinsic stability of a drug that is foundational to the development and validation of stability-indicating analytical methods. There is a lack of clarity in the scientific literature and regulatory guidance as to what constitutes an "appropriate" endpoint to a set of stress experiments. That is, there is no clear agreement regarding how to determine if a sample has been sufficiently stressed. Notably, it is unclear what represents a suitable justification for declaring a drug substance (DS) or drug product (DP) "stable" to a specific forced degradation condition. To address these concerns and to ensure all pharmaceutically-relevant, potential degradation pathways have been suitably evaluated, we introduce a two-endpoint classification designation supported by experimental data. These two endpoints are 1) a % total degradation target outcome (e.g., for "reactive" drugs) or, 2) a specified amount of stress, even in the absence of any degradation (e.g., for "stable" drugs). These recommended endpoints are based on a review of the scientific literature, regulatory guidance, and a forced degradation data set from ten global pharmaceutical companies. The experimental data set, derived from the Campbell et al. (2022) benchmarking study,1 provides justification for the recommendations. Herein we provide a single source reference for small molecule DS and DP forced degradation stress conditions and endpoint best practices to support regulatory submissions (e.g., marketing applications). Application of these forced degradation conditions and endpoints, as part of a well-designed, comprehensive and a sufficiently rigorous study plan that includes both the DS and DP, provides comprehensive coverage of pharmaceutically-relevant degradation and avoids unreasonably extreme stress conditions and drastic endpoint recommendations sometimes found in the literature.

Developing In Situ Chemometric Models with Raman Spectroscopy for Monitoring an API Disproportionation with a Complex Polymorphic Landscape.

An in situ Raman method was developed to characterize the disproportionation of two salts involving a complex polymorphic landscape comprising up to two metastable and one stable freebase forms. Few precedents exist for Raman calibration procedures for solid form quantitation involving more than two polymorphs, while no literature examples were found for cases with multiple metastable forms. Therefore, a new Raman calibration procedure was proposed by directly using disproportionation experiments to generate multiple calibration samples encompassing a range of polymorph ratios through in-line Raman measurements complemented by off-line reference X-ray diffraction measurements. The developed Raman methods were capable of accurately quantitating each solid form in situ when solid concentration variation was incorporated into the calibration dataset. The kinetic understanding of the thermodynamically driven polymorphic conversions gained from this Raman method guided the selection of the salt best suited for the delivery of the active ingredient in the drug product. This work provided a spectroscopic and mathematical approach for simultaneously quantitating multiple polymorphs from a complex mixture of solids with the objective of real-time monitoring.

NIR spectroscopic methods for monitoring blend potency in a feed frame - calibration transfer between offline and inline using a continuum regression filter.

A material sparing method for near-infrared (NIR) calibration was developed using an offline apparatus coupled with a calibration transfer method to enable a partial least squares (PLS) model to monitor the concentration of active pharmaceutical ingredients (API) in the feed frame of a rotary tablet press. The offline apparatus was designed to simulate the powder flow dynamic and NIRS measurement environment of a tablet-press feed frame. A comprehensive experimental design, including calibration and testing, was employed to determine blend inhomogeneity. NIR spectra were collected at both the feed frame (inline) conditions and the simulator (offline) conditions. The simulator conditions were designed to mimic the density and powder flow in the feed frame during the actual tableting process. The offline data were pretreated by an orthogonalization-based calibration transfer algorithm, a continuum regression filter (CR filter), before being subjected to PLS modeling. This study demonstrated: (1) calibration for inline application can be generated using an offline apparatus, and (2) the CR filter, as an innovative calibration transfer method, can generalize the offline method for multiple feed frame conditions.

Application of Process Analytical Technology for Pharmaceutical Coating: Challenges, Pitfalls, and Trends.

Coating process is a critical unit operation for manufacturing solid oral dosage forms. For a long time, the coating weight gain has been discerned as the most important, if not only, characteristic describing the coating quality. As the introduction of quality by design (QbD) and advancement of process analytical technology (PAT), nowadays more techniques are available to analyze other quality attributes which have been overlooked but have substantial impacts on the performance of coated products. The techniques that permit rapid and non-destructive measurements are of particular importance to improve process operation and product quality. This article reviews the analytical techniques that have been and potentially could be used as PAT tools for characterizing the quality of pharmaceutical coating product. By identifying the challenges and pitfalls encountered during PAT application, the review aims at fostering the adoption of PAT for paving the way to enhanced quality and efficiency of the coating processes.

Terahertz Time of Flight Spectroscopy as a Coating Thickness Reference Method for Partial Least Squares Near Infrared Spectroscopy Models.

Near infrared spectroscopy (NIRS) is often used during the tablet coating process to assess coating thickness. As the coating process proceeds, the increase and decrease in NIRS signal from both the coating formulation and tablet core has been related to coating thickness. Partial least-squares models are often generated relating NIRS spectra to reference coating thickness measurements for in-line and/or at-line monitoring of the coating process. This study investigated the effect of the reference coating thickness measurements on the accuracy of the model. The two primary reference techniques used were weight gain-based coating thickness and terahertz-based coating thickness. Most NIRS coating thickness models currently use weight gain-based reference values; however, terahertz-time-of-flight spectroscopy (THz-TOF) offers a more direct reference coating thickness measurement. Results showed that the accuracy of the NIRS coating thickness model significantly improved when terahertz-based coating thickness measurements were used as reference when compared to weight gain-based coating thickness measurements. Therefore, the application of THz-TOF as a reference method is further demonstrated.

Determining the effect of photodegradation on film coated nifedipine tablets with terahertz based coating thickness measurements.

Film coating of nifedipine tablets is commonly performed to reduce photo-degradation. The coating thickness of these tablets is a primary dictating factor of photo-stability. Terahertz spectroscopy enables accurate measurement of coating thickness. This study identifies a method to determine an end-point of a photo-protective coating process by using coating thickness measurements from terahertz time of flight spectroscopy (THz-TOF). For this method, nifedipine tablets, at different coating thicknesses, were placed in a photostability chamber. The illumination conditions of the coated tablets were adjusted based on the time duration of these tablets inside the chamber. A multiple linear regression model was developed with the coating thickness estimates from THz-TOF and illumination conditions information to predict the amount of drug remaining after photo-degradation (percent label claim). The prediction error of this model was 1.03% label claim in the range of 88.4-100.6% label claim. According to this model, acceptable levels of photo-protection in illumination conditions of up to approximately 700,000 lx hours was achieved at the end of the coating process (approximately 50 µm coating thickness) performed in this study. These results suggest THz-TOF as a viable process analytical technology tool for process understanding and end-point determination of a photo-protective coating process.

Refractive Index Measurement of Pharmaceutical Solids: A Review of Measurement Methods and Pharmaceutical Applications.

Refractive index is an important optical parameter that can be used to characterize the physicochemical properties of pharmaceutical solids. The complexity of most drugs and solid oral dosage systems introduces challenges for refractive index measurement methods. These challenges are highlighted, and different types of measurement methods are discussed in this review article. These measurements provide pharmaceutical scientists the opportunity to improve the drug-development process and enhance product quality. Pharmaceutical applications range from identification and quantification of drug crystallinity and polymorphism to mechanical strength assessment of tablets. This review article surveys the literature and evaluates the current and potential future characterization of pharmaceutical solids using refractive index measurements.

Feedforward and Feedback Control of a Pharmaceutical Coating Process.

This work demonstrates the use of a combination of feedforward and feedback loops to control the controlled release coating of theophylline granules. Feedforward models are based on the size distribution of incoming granules and are used to set values for the airflow in the fluid bed processor and the target coat weight to be applied to the granules. The target coat weight of the granules is controlled by a feedback loop using NIR spectroscopy to monitor the progress of the process. By combining feedforward and feedback loops, significant variation in the size distributions and ambient conditions were accommodated in the fluid bed coating of the granules and a desired dissolution profile was achieved. The feedforward component of the control system was specifically tested by comparing the performance of the control system with and without this element by Monte Carlo simulation.

A robust quantitative near infrared modeling approach for blend monitoring.

This study demonstrates a material sparing Near-Infrared modeling approach for powder blend monitoring. In this new approach, gram scale powder mixtures are subjected to compression loads to simulate the effect of scale using an Instron universal testing system. Models prepared by the new method development approach (small-scale method) and by a traditional method development (blender-scale method) were compared by simultaneously monitoring a 1kg batch size blend run. Both models demonstrated similar model performance. The small-scale method strategy significantly reduces the total resources expended to develop Near-Infrared calibration models for on-line blend monitoring. Further, this development approach does not require the actual equipment (i.e., blender) to which the method will be applied, only a similar optical interface. Thus, a robust on-line blend monitoring method can be fully developed before any large-scale blending experiment is viable, allowing the blend method to be used during scale-up and blend development trials.