Small-Angle X-ray Scattering (SAXS) Used for the Identification of Nicomorphine Polymorphic Changes at the Early Stage to Avoid Varied Stability and Possible Side Effects.

In this paper, we present the identification of polymorphisms at an early stage, identified by applying non-standard methods such as SAXS. We provide an analytical approach to polymorphism in the quality/purity of an active pharmaceutical ingredient (API), supplied to a generic company by two different suppliers (i.e., manufacturers). Changes in thermodynamic polymorphism firstly become visible in traces in the larger crystal lattices, which are visible on the SAXS spectrum only using the logarithmic scale, as shown in the result figures. Hence, we are here on the trail of the beginning of a new polymorph in nicomorphine, whose crystal waviness at the early stage is visible only in the additional symmetrical peaks identified and calculated using SAXS, while the chemical analyses excluded all kinds of chemical impurities. The chemical and structural properties were studied using the following techniques: SAXS, WAXS, DSC, dissolution, Raman spectroscopy, and FTIR. Only the SAXS technique could identify crucial differences and calculate the additional signals related to giant crystals, whilst a standard method such as WAXS showed none, and nor did the chemical analyses, such as Raman spectroscopy and FT-IR. This means that due to water in crystallization (known in nicomorphine) or thermodynamic waviness, the formation of the new polymorph starts first in traces, which become visible at larger distances from the crystal lattice, detectible only in the SAXS range. This is a very important premise and hypothesis for further research, and we believe that this work lays a new stone in understanding the origin of new unknown polymorphs and their mixtures. Therefore, the aim of this work is to show that the use of non-standard methods (i.e., SAXS) can be of great benefit to API analysis and the identification of polymorphic changes in the early phase, which can cause varied stability, solubility and bioavailability and thus different therapeutic effects or side effects.

Liquid API feeding in pharmaceutical HME: Novel options in solid dosage manufacturing.

Hot melt extrusion (HME) is a common unit operation. It is broadly applicable in the pharmaceutical industry and can be implemented in a continuous manufacturing line. However, the conventional way of active pharmaceutical ingredient (API) feeding with a pre-blend consisting of a powdered API and a polymer does not allow the flexibility and agility to adjust the process parameters, which is generally an essential part of continuous manufacturing. In addition, this method of API feeding may result in the segregation of the individual powder components or agglomeration of highly cohesive materials, leading to an inhomogeneous API content in the extrudates, especially at low doses. In this study, the universal applicability of liquid side feeding in pharmaceutical HME was demonstrated using various APIs suspended or dissolved in water and fed as suspension or undersaturated, supersaturated, and highly concentrated solutions into anterior parts of the extruder. The extrudates were characterized in terms of their API content, residual moisture content, and solid-state of the API embedded in the polymer. The results show that a uniform API content without major deviations can be obtained via this method. Furthermore, the residual moisture content of the extrudates was low enough to have no significant influence on further processing of the final dosage form. In summary, this advanced way of feeding allows an accurate, flexible, and agile feeding of APIs, facilitating the production of personalized final dosage forms and a novel option to link the manufacturing of the drug substance and the drug product.

Toward a new generation of vaginal pessaries via 3D-printing: Concomitant mechanical support and drug delivery.

To improve patient adherence, vaginal pessaries - polymeric structures providing mechanical support to treat stress urinary incontinence (SUI) - greatly benefit from 3D-printing through customization of their mechanics, e.g. infill modifications. However, currently only limited polymers provide both flawless printability and controlled drug release. The current study closes this gap by exploring 3D-printing, more specifically fused filament fabrication, of pharmaceutical grade thermoplastic polyurethanes (TPU) of different hardness and hydrophilicity into complex pessary structures. Next to the pessary mechanics, drug incorporation into such a device was addressed for the first time. Mechanically, the soft hydrophobic TPU was the most promising candidate for pessary customization, as pessaries made thereof covered a broad range of the key mechanical parameter, while allowing self-insertion. From the drug release point of view, the hydrophobic TPUs were superior over the hydrophilic one, as the release levels of the model drug acyclovir were closer to the target value. Summarizing, the fabrication of TPU-based pessaries via 3D-printing is an innovative strategy to create a customized pessary combination product that simultaneously provides mechanical support and pharmacological therapy.

Personalised urethra pessaries prepared by material extrusion-based additive manufacturing.

Material extrusion-based additive manufacturing, commonly referred to as 3D-printing, is regarded as the key technology to pave the way for personalised medical treatment. This study explores the technique's potential in customising vaginal inserts with complex structures, so-called urethra pessaries. A novel, flawlessly 3D-printable and biocompatible polyester-based thermoplastic elastomer serves as the feedstock. Next to the smart selection of the 3D-printing parameters cross-sectional diameter and infill to tailor the pessary's mechanical properties, we elaborate test methods accounting for its application-specific requirements for the first time. The key property, i.e. the force the pessary exerts on the urethra to relief symptoms of urinary incontinence, is reliably adjusted within a broad range, including that of the commercial injection-moulded silicone product. The pessaries do not change upon long-term exposure to vaginal fluid simulant and compression (in-vivo conditions), satisfying the needs of repeated pessary use. Importantly, the vast majority of the 3D-printed pessaries allows for self-insertion and self-removal without any induced pessary rupture. Summarising, 3D-printed pessaries are not only a reasonable alternative to the commercial products, but build the basis to effectively treat inhomogeneous patient groups. They make the simple but very effective pessary therapy finally accessible to every woman.

Towards predicting the product quality in hot-melt extrusion: Pilot plant scale extrusion.

Following our study on the impact of hot melt extrusion (HME) process conditions on the product quality, we expanded our investigation to assessing the effect of scale-up on the product quality. To this end, we studied the influence of process settings and different scale-up variants on the active pharmaceutical ingredient (API) degradation in a pilot plant scale extruder. Six scale-up variants were investigated and none of them could replicate the product quality from the original process setup on a lab-scale extruder. By analyzing several process-dependent and -independent variables and cross referencing them to the experiments in the lab-scale extruder, we identified certain patterns. The results of the reduced order mechanistic 1D HME simulation of various process states made it possible to establish a correlation between the achieved API degradation and the local melt temperature and the exposure time in specific zones along the screw configuration. Since the same melt temperature and exposure time correlations were also valid for the lab scale-extruder, such an approach could be used in the future to predict the product quality as a function of processing conditions fully in silico prior to the first extrusion trials.

Development of Porous Polyurethane Implants Manufactured via Hot-Melt Extrusion.

Implantable drug delivery systems (IDDSs) offer good patient compliance and allow the controlled delivery of drugs over prolonged times. However, their application is limited due to the scarce material selection and the limited technological possibilities to achieve extended drug release. Porous structures are an alternative strategy that can overcome these shortcomings. The present work focuses on the development of porous IDDS based on hydrophilic (HPL) and hydrophobic (HPB) polyurethanes and chemical pore formers (PFs) manufactured by hot-melt extrusion. Different PF types and concentrations were investigated to gain a sound understanding in terms of extrudate density, porosity, compressive behavior, pore morphology and liquid uptake. Based on the rheological analyses, a stable extrusion process guaranteed porosities of up to 40% using NaHCO3 as PF. The average pore diameter was between 140 and 600 µm and was indirectly proportional to the concentration of PF. The liquid uptake of HPB was determined by the open pores, while for HPL both open and closed pores influenced the uptake. In summary, through the rational selection of the polymer type, the PF type and concentration, porous carrier systems can be produced continuously via extrusion, whose properties can be adapted to the respective application site.

Towards predicting the product quality in hot-melt extrusion: Small scale extrusion.

In product development, it is crucial to choose the appropriate drug manufacturing route accurately and timely and to ensure that the technique selected is suitable for achieving the desired product quality. Guided by the QbD principles, the pharmaceutical industry is currently transitioning from batch to continuous manufacturing. In this context, process understanding and prediction are becoming even more important. With regard to hot melt extrusion, the process setup, optimization and scale-up in early stages of product development are particularly challenging due to poor process understanding, complex product-process relationship and a small amount of premix available for extensive experimental studies. Hence, automated, quick and reliable process setup and scale-up requires simulation tools that are accurate enough to capture the process and determine the product-process relationships. To this end, the effect of process settings on the degradation of the active pharmaceutical ingredient (API) in a lab-scale Leistritz ZSE12 extruder was investigated. As part of the presented study, the limitations of traditional process analysis using integral process values were investigated, together with the potential that simulations may have in predicting the process performance and the product quality. The results of our investigation indicate that the average melt temperatures and the exposure times in specific zones along the screw configuration correlate well with the API degradation values and can be used as potent process design criteria to simplify the process development.

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion.

To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV-Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.

Controlled-Release from High-Loaded Reservoir-Type Systems-A Case Study of Ethylene-Vinyl Acetate and Progesterone.

Reservoir systems (drug-loaded core surrounded by drug-free membrane) provide long-term controlled drug release. This is especially beneficial for drug delivery to specific body regions including the vagina. In this study, we investigated the potential of reservoir systems to provide high drug release rates over several weeks. The considered model system was an intra-vaginal ring (IVR) delivering progesterone (P4) in the mg/day range using ethylene-vinyl acetate (EVA) as release rate-controlling polymers. To circumvent the high material needs associated with IVR manufacturing, we implemented a small-scale screening procedure that predicts the drug release from IVRs. Formulations were designed based on the solubility and diffusivity of P4 in EVAs with varying vinyl acetate content. High in-vitro P4 release was achieved by i) high P4 solubility in the core polymer; ii) high P4 partition coefficient between the membrane and the core; and/or iii) low membrane thicknesses. It was challenging for systems designed to release comparatively high fractions of P4 at early times to retain a constant drug release over a long time. P4 crystal dissolution in the core could not counterbalance drug diffusion through the membrane and drug crystal dissolution was found to be the rate-limiting step. Overall, high P4 release rates can be achieved from EVA-based reservoir systems.

Establishment of a Molding Procedure to Facilitate Formulation Development for Co-extrudates.

Co-extrusion offers a number of advantages over conventional manufacturing techniques. However, the setup of a co-extrusion line is cost- and time-intense and formulation development is challenging. This work introduces a novel procedure to test the applicability of a co-extruded reservoir-type system at an early product development stage. We propose vacuum compression molding (VCM), a fast procedure that requires only small material amounts, for the manufacturing of cylindrical reservoir-type system. To this end, the commercially available co-extruded product NuvaRing® and variations thereof were used as test systems. All VCM systems showed a homogeneous skin thickness that adhered well to the core, thereby providing a precise core/skin interface. As drug release is a key criterion for pharmaceutical products, a modified in vitro dissolution method was set up to test the VCM systems. The drug release from the VCM systems was in the same order of magnitude as the corresponding co-extruded strands and followed the same release kinetics. Moreover, the VCM systems were capable of indicating the relative effect of formulation-related modifications on drug release. Overall, this shows that this system is a powerful tool that facilitates formulation tailoring and co-extrusion process setup at the earliest stage.

Development and evaluation of accelerated drug release testing methods for a matrix-type intravaginal ring.

Accelerated drug release testing is a valuable quality control tool for long-acting non-oral extended release formulations. Currently, several intravaginal ring candidates designed for the long-term delivery of steroids or anti-infective drugs are being in the developing pipeline. The present article addresses the demand for accelerated drug release methods for these formulations. We describe the development and evaluation of accelerated release methods for a steroid releasing matrix-type intravaginal ring. The drug release properties of the formulation were evaluated under real-time and accelerated test conditions. Under real-time test conditions drug release from the intravaginal ring was strongly affected by the steroid solubility in the release medium. Under sufficient sink conditions that were provided in release media containing surfactants drug release was Fickian diffusion driven. Both temperature and hydro-organic dissolution media were successfully employed to accelerate drug release from the formulation. Drug release could be further increased by combining the temperature effect with the application of a hydro-organic release medium. The formulation continued to exhibit a diffusion controlled release kinetic under the investigated accelerated conditions. Moreover, the accelerated methods were able to differentiate between different prototypes of the intravaginal ring that exhibited different release profiles under real-time test conditions. Overall, the results of the present study indicate that both temperature and hydro-organic release media are valid parameters for accelerating drug release from the intravaginal ring. Variation of either a single or both parameters yielded release profiles that correlated well with real-time release.