Statistical data treatment for residence time distribution studies in pharmaceutical manufacturing.

Residence time distribution (RTD) method has been widely used in the pharmaceutical manufacturing for understanding powder dynamics within unit operations and continuous integrated manufacturing lines. The dynamics thus captured is then used to develop predictive models for unit operations and important RTD-based applications ensuring product quality assurance. Despite thorough efforts in tracer selection, data acquisition, and calibration model development to obtain tracer concentration profiles for RTD studies, there can exist significant noise in these profiles. This noise can make it challenging to identify the underlying signal and get a representative RTD of the system under study. Such concerns have previously indicated the importance of noise handling for RTD measurements in literature. However, the literature does not provide sufficient information on noise handling or data treatment strategies for RTD studies. To this end, we investigate the impact of varying levels of noise using different tracers on measurement of RTD profile and its applications. We quantify the impact of different denoising methods (time and frequency averaging methods). Through this investigation, we see that Savitsky Golay filtering turns out to a good method for denoising RTD profiles despite varying noise levels. The investigation is performed such that the key features of the RTD profile (which are important for RTD based applications) are preserved. Subsequently, we also investigate the impact of denoising on RTD-based applications such as out-of-specification (OOS) analysis and RTD modeling. The results show that the degree of noise levels considered in this work do not significantly impact the RTD-based applications.

Optimal quantification of residence time distribution profiles from a quality assurance perspective.

Residence time distribution (RTD) has been widely applied across various fields of chemical engineering, including pharmaceutical manufacturing, for applications such as material traceability, quality assurance, system health monitoring, and fault detection. Determination of a representative RTD, in principle, requires an accurate process analytical technology (PAT) procedure capturing the entire range of tracer concentrations from zero to maximum. Such a wide concentration range creates at least two problems: i) decreased accuracy of the model across the entire range of concentrations, relating to limit of quantification, and ii) ambiguity associated with the detection of the tracer for low concentration levels, relating to limit of detection (LOD). These problems affect not only the RTD profile itself, but also RTD-based applications, which can potentially lead to erroneous conclusions. This article seeks to minimize the impact of these problems by understanding the relative importance of different features of RTD on the detection of out-of-specification (OOS) products. In this work, the RTD obtained experimentally was truncated at different levels, to investigate the impact of the truncation of RTD on funnel plots for OOS detection. The main finding is that the tail of the RTD can be truncated with no loss of accuracy in the determination of exclusion intervals. This enables the manufacturing scientist to focus entirely on the peak region, maximizing the accuracy of chemometric models.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: III. Impact of drug nanoparticle loading.

Polymer strip films have emerged as a robust platform for poorly water-soluble drug delivery. However, the common conception is that films cannot exceed low drug loadings, mainly due to poor drug stability, slow release, and film brittleness. This study explores the ability to achieve high loadings of poorly water-soluble drug nanoparticles in strip films while retaining good mechanical properties and enhanced dissolution rate. Aqueous suspensions containing up to 30wt% griseofulvin nanoparticles were prepared via wet stirred media milling and incorporated into hydroxypropyl methylcellulose (HPMC) films. Griseofulvin loading in films was adjusted to be between 9 and 49wt% in HPMC-E15 films and 30 and 73wt% in HPMC-E4M films by varying the mixing ratio of HPMC solution-to-griseofulvin suspension. All films exhibited good content uniformity and nanoparticle redispersibility up to 50wt% griseofulvin, while E4M films above 50wt% griseofulvin had slightly worse content uniformity and poor nanoparticle redispersibility. Increasing drug loading in films generally required more time to achieve 100% release during dissolution, although polymer-drug clusters dispersed from E4M films above 50wt% griseofulvin, resulting in similar dissolution profiles. While all films exhibited good tensile strength, a significant decrease in percent elongation was observed above 40-50wt% GF, resulting in brittle films.

Critical Material Attributes of Strip Films Loaded With Poorly Water-Soluble Drug Nanoparticles: II. Impact of Polymer Molecular Weight.

Recent work established polymer strip films as a robust platform for delivery of poorly water-soluble drug particles. However, a simple means of manipulating rate of drug release from films with minimal impact on film mechanical properties has yet to be demonstrated. This study explores the impact of film-forming polymer molecular weight (MW) and concentration on properties of polymer films loaded with poorly water-soluble drug nanoparticles. Nanoparticles of griseofulvin, a model Biopharmaceutics Classification System class II drug, were prepared in aqueous suspension via wet stirred media milling. Aqueous solutions of 3 viscosity grades of hydroxypropyl methylcellulose (14, 21, and 88 kDa) at 3 viscosity levels (∼9500, ∼12,000, and ∼22,000 cP) were mixed with drug suspension, cast, and dried to produce films containing griseofulvin nanoparticles. Few differences in film tensile strength or elongation at break were observed between films within each viscosity level regardless of polymer MW despite requiring up to double the time to achieve 100% drug release. This suggests film-forming polymer MW can be used to manipulate drug release with little impact on film mechanical properties by matching polymer solution viscosity. In addition, changing polymer MW and concentration had no negative impact on drug content uniformity or nanoparticle redispersibility.

Critical material attributes (CMAs) of strip films loaded with poorly water-soluble drug nanoparticles: I. Impact of plasticizer on film properties and dissolution.

Recent studies have demonstrated polymer films to be a promising platform for delivery of poorly water-soluble drug particles. However, the impact of critical material attributes, for example plasticizer, on the properties of and drug release from such films has yet to be investigated. In response, this study focuses on the impact of plasticizer and plasticizer concentration on properties and dissolution rate of polymer films loaded with poorly water-soluble drug nanoparticles. Glycerin, triacetin, and polyethylene glycol were selected as film plasticizers. Griseofulvin was used as a model Biopharmaceutics Classification System class II drug and hydroxypropyl methylcellulose was used as a film-forming polymer. Griseofulvin nanoparticles were prepared via wet stirred media milling in aqueous suspension. A depression in film glass transition temperature was observed with increasing plasticizer concentration, along with a decrease in film tensile strength and an increase in film elongation, as is typical of plasticizers. However, the type and amount of plasticizer necessary to produce strong yet flexible films had no significant impact on the dissolution rate of the films, suggesting that film mechanical properties can be effectively manipulated with minimal impact on drug release. Griseofulvin nanoparticles were successfully recovered upon redispersion in water regardless of plasticizer or content, even after up to 6months' storage at 40°C and 75% relative humidity, which contributed to similar consistency in dissolution rate after 6months' storage for all films. Good content uniformity (<4% R.S.D. for very small film sample size) was also maintained across all film formulations.

Preparation and characterization of fast dissolving pullulan films containing BCS class II drug nanoparticles for bioavailability enhancement.

The aim of this study is to assess pullulan as a novel steric stabilizer during the wet-stirred media milling (WSMM) of griseofulvin, a model poorly water-soluble drug, and as a film-former in the preparation of strip films via casting-drying the wet-milled drug suspensions for dissolution and bioavailability enhancement. To this end, pullulan films, with xanthan gum (XG) as thickening agent and glycerin as plasticizer, were loaded with griseofulvin nanoparticles prepared by WSMM using pullulan in combination with sodium dodecyl sulfate (SDS) as an ionic stabilizer. The effects of drug loading and milling time on the particle size and suspension stability were investigated, as well as XG concentration and casting thickness on film properties and dissolution rate. The nanosuspensions prepared with pullulan-SDS combination were relatively stable over 7 days; hence, this combination was used for the film preparation. All pullulan-based strip films exhibited excellent content uniformity (most <3% RSD) despite containing only 0.3-1.3 mg drug, which was ensured by the use of precursor suspensions with >5000 cP viscosity. USP IV dissolution tests revealed fast/immediate drug release (t80 < 30 min) from films <120 µm thick. Thinner films, films with lower XG loading, or smaller drug particles led to faster drug dissolution, while drug loading had no discernible effect. Overall, these results suggest that pullulan may serve as an acceptable stabilizer for media milling in combination with surfactant as well as a fast-dissolving film former for the fast release of poorly water-soluble drug nanoparticles.

Polymer strip films as a robust, surfactant-free platform for delivery of BCS Class II drug nanoparticles.

The robustness of the polymer strip film platform to successfully deliver a variety of BCS Class II drug nanoparticles without the need for surfactant while retaining positive characteristics such as nanoparticle redispersibility and fast dissolution is demonstrated. Fenofibrate (FNB), griseofulvin (GF), naproxen (NPX), phenylbutazone (PB), and azodicarbonamide (AZD) were considered as model poorly water-soluble drugs. Their aqueous nanosuspensions, produced via wet stirred media milling, were mixed with hydroxypropyl methylcellulose solution containing glycerin as plasticizer, followed by casting and drying to form films. For the purpose of comparison, sodium dodecyl sulfate (SDS) was used as surfactant, but was found to be unnecessary for achieving fast dissolution (t80 between 18 and 28 min) for all five drugs. Interestingly, SDS was required for the full recovery of nanoparticles for PB, yet lack of it did not impact the dissolution. Interactions between drug and polymer were investigated with FTIR spectroscopy whereas drug crystallinity within the film was investigated via Raman spectroscopy. Films for all drugs, even for very small samples, exhibited excellent content uniformity (RSD <4%) regardless of use of surfactant. Overall, these results demonstrate the novelty and robustness of the polymer strip film platform for fast release of poorly water-soluble drugs without requiring any surfactants.