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The supply of affordable, high-quality pharmaceuticals to US patients has been on a critical path for decades. In and beyond the COVID-19 pandemic, this critical path has become tortuous. To regain reliability, reshoring of the pharmaceutical supply chain to the USA is now a vital national security need. Reshoring the pharmaceutical supply with old know-how and outdated technologies that cause inherent unpredictability and adverse environmental impact will neither provide the security we seek nor will it be competitive and affordable. The challenge at hand is complex akin to redesigning systems, including corporate and public research and development, manufacturing, regulatory, and education ones. The US academic community must be engaged in progressing solutions needed to counter emergencies in the COVID-19 pandemic and in building new methods to reshore the pharmaceutical supply chain beyond the pandemic.

Facilitating utility of prior knowledge to accelerate evidence-based new drug development is a focus of several communities of knowledge, such as clinical pharmacology. For example, progress has been made via modeling and simulation of pharmacokinetic and pharmacodynamic relationships in the more effective use of “End of Phase 2” regulatory meetings for a New Drug Application (NDA). Facilitating utility of prior “Chemistry, Manufacturing, and Controls” (CMC) knowledge to accelerate new drug development and regulatory review process is also a topic of significant interest. This paper focuses on facilitating the utility of prior pharmaceutical formulation knowledge to accelerate drug product development and regulatory review of generic and biosimilar products. This knowledge is described as New Prior Knowledge (NPK) because research is often needed to fill ontological (i.e., the domain of connectivity between concepts and phenomena), epistemological (i.e., distinguishing knowledge or justified belief from the opinion), and methodological gaps in information derived a decade or so ago. The corporate economic advantages of such knowledge are derived, in part, when significant portions remain a trade secret. The proposed NPK seeks to generate knowledge about critical aspects of pharmaceutical quality and failure modes to place it in the public domain and to facilitate accelerated and more confident development and regulatory review of generic products. The paradoxical combination of “new” and “prior knowledge” is chosen deliberately to highlight both a distinction from proprietary and trade secret information and to acknowledge certain historical dogmas inherent in the current practices. Considerations for operationalizing NPK are also summarized.

This review gives a brief overview about microbial contamination in pharmaceutical products. We discuss the distribution and potential sources of microorganisms in different areas, ranging from manufacturing sites, pharmacy stores, hospitals, to the post-market phase. We also discuss the factors that affect microbial contamination in popular dosage forms (e.g., tablets, sterile products, cosmetics). When these products are contaminated, the microorganisms can cause changes. The effects range from mild changes (e.g., discoloration, texture alteration) to severe effects (e.g., changes in activities, toxicity). The most common method for countering microbial contamination is the use of preservatives. We review some frequently used preservatives, and we describe the mechanisms by which microorganisms develop resistance to these preservatives. Finally, because preservatives are inherently toxic, we review the efforts of researchers to utilize water activity and other non-preservative approaches to combat microbial contamination.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro–in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Controlled release of drugs is an important strategy to diminish the drug dose and adverse side effects. Aqueous mixtures of polysaccharides and proteins are usually unstable above a certain biopolymer concentration and phase separation occurs either because of repulsive (segregative) or attractive (associative) interactions. Herein, pectin/casein microcapsules were prepared by complex coacervation aiming at prolonged drug release. The morphological characteristics, particle size, distribution, and release kinetics of microcapsules were studied using as a model the hydrophilic drug acetaminophen. It was detected that complexation of pectin/casein particles occurs at pH values lower than 6, resulting in the formation of spherical particles after spray drying. Microcapsules had a mean diameter of 3.138 and 4.929 μm without drug, and of 4.680 and 5.182 μm with drug using USP and 8003 pectin, respectively. The in vitro release of acetaminophen from microcapsules was slow and the drug release mechanism was controlled by diffusion following first-order kinetics. There was greater release of acetaminophen in simulated gastric fluid than simulated intestinal fluid conditions. Concluding, the polymeric system present herein seemed to be appropriate for a prolonged release of acetaminophen throughout the gastrointestinal tract. Nevertheless, it is likely that it is a promising pectin/casein complex for lipossoluble drugs, which merits further investigation.

The present research work was aimed to formulate clotrimazole encapsulated Cavamax W7 composite ethosomes by injection method for improved delivery across epidermis. 3(2) factorial design was used to design nine formulations (F1-F9) and compared with ethosomal formulations (F10-F12). F9 with vesicle size of 202.8 ± 4.8 nm, highest zeta potential (-83.6 ± 0.96 mV) and %EE of 98.42 ± 0.15 was selected as optimized composite ethosome and F12 as reference ethosomal formulation. As revealed by transmission electron microscopy F9 vesicles were more condensed, uniformly spherical in shape than F12 vesicles. Vesicular stability studies indicated F9 to be more stable as compared to F12. Both F9 and F12 were incorporated in carbopol 934 gel base to get G1-G8 gel formulations and evaluated for in vitro skin permeability. Cavamax W7 composite ethosomal optimized gel (G5) showed higher in vitro percent cumulative drug permeation (88.53 ± 2.10%) in 8 h and steady state flux (J(ss)) of 3.39 ± 1.45 μg/cm(2)/min against the J(ss) of 1.57 ± 0.23 μg/cm(2)/min for ethosomal gel (G1) and 1.13 ± 0.06 μg/cm(2)/min for marketed formulation. The J(ss) flux of G5 was independent of amount of drug applied/unit area of skin. In vivo confocal laser scanning microscopic study of G5 depicted uniform and deeper penetration of rhodamine B (marker) in epidermis from Cavamax W7 composite ethosomal gel in comparison to G1. Finally, G5 demonstrated better (p0.05) antifungal activity against Candida albicans and Aspergillus niger than G1 thus, signifying that Cavamax W7 composite ethosomes present a superior stable and efficacious vesicular system than ethosomal formulation for topical delivery of clotrimazole.

Developed approximately 100 years ago for natural rubber/plastics applications, processes via twin screw extrusion (TSE) now generate some of the most cutting-edge drug delivery systems available. After 25 or so years of usage in pharmaceutical environments, it has become evident why TSE processing offers significant advantages as compared to other manufacturing techniques. The well-characterized nature of the TSE process lends itself to ease of scale-up and process optimization while also affording the benefits of continuous manufacturing. Interestingly, the evolution of twin screw extrusion for pharmaceutical products has followed a similar path as previously trodden by plastics processing pioneers. Almost every plastic has been processed at some stage in the manufacturing train on a twin screw extruder, which is utilized to mix materials together to impart desired properties into a final part. The evolution of processing via TSEs since the early/mid 1900s is recounted for plastics and also for pharmaceuticals from the late 1980s until today. The similarities are apparent. The basic theory and development of continuous mixing via corotating and counterrotating TSEs for plastics and drug is also described. The similarities between plastics and pharmaceutical applications are striking. The superior mixing characteristics inherent with a TSE have allowed this device to dominate other continuous mixers and spurred intensive development efforts and experimentation that spawned highly engineered formulations for the commodity and high-tech plastic products we use every day. Today, twin screw extrusion is a battle hardened, well-proven, manufacturing process that has been validated in 24-h/day industrial settings. The same thing is happening today with new extrusion technologies being applied to advanced drug delivery systems to facilitate commodity, targeted, and alternative delivery systems. It seems that the “extrusion evolution” will continue for wide-ranging pharmaceutical products.

The influence of experimental temperature on the permeability of model diffusants across porcine buccal mucosa was investigated in vitro. The permeability increased significantly as the experimental temperature was increased in increments of approximately 7°C. It was observed that the apparent permeability and temperature were related by an exponential relationship that conformed to the Arrhenius equation. Diffusants with higher lipophilicities--buspirone and bupivacaine--had lower activation energies for diffusion when compared to hydrophilic diffusants--antipyrine and caffeine. The activation energy for diffusion of the model diffusants decreased linearly with increasing distribution coefficients across porcine buccal mucosa. The results suggested that the buccal mucosa acts as a stronger barrier to the diffusion of hydrophilic diffusants than the lipophilic ones. The log-linear relationship between permeability and temperature indicates that temperature should be carefully controlled in diffusion experiments. These results also point to the possibility of developing heat-generating buccal delivery devices, especially for hydrophobic diffusants.

A pharmaceutical formulation typically contains one or more excipients in addition to the active pharmaceutical ingredient(s). Though excipients have been considered inert components of a formulation, variability in their properties has been shown to affect the performance of drug dosage forms and delivery systems. This study investigates the inter- and intra-manufacturer variability among different NF grades and lots of xanthan gum made by two manufacturers. As many formulators rely on compendial standards to monitor and control the variability of excipients, this study focuses on the adequacy of the NF specifications, in particular the viscosity specification, to discern the variability in solution properties of different pharmaceutical grades and lots of xanthan gum. All the grades and lots in this study were NF grade materials. Xanthan gum solutions were prepared in accordance with NF test methodology and were rheologically evaluated using a rotational rheometer. Both steady shear measurements and small amplitude oscillatory measurements were carried out on 1% w/w xanthan gum solutions. Results showed significant inter- and intra-manufacturer variability among the NF grades and lots of xanthan gum that was not reflected in the NF viscosity test specifications.

The Food and Drug Administration (FDA) approved the New Drug Application for Wellbutrin sustained release (SR) 100 mg tablets on October 4, 1996. However, by 1998, the FDA expressed concern about the stability of this drug product based on an increase in the dissolution profile on storage. Data submitted in the annual report showed that this drug product could not meet the expiry of 18 months at the International Committee on Harmonization storage condition of 25 degrees C/60% relative humidity. The FDA mandated a 12-month expiry and GlaxoWellcome tightened this further by instituting an expiry of 9 months. The FDA also requested a long-term solution to the stability of Wellbutrin SR 100 mg tablets. Investigations via colloidal solutions revealed that the dissolution rate increase on storage occurred due to acid hydrolysis of the release controlling polymer. This drug product was successfully reformulated by slowing the initial dissolution rate and having an increased ratio of release controlling polymer to acid stabilizer. The reformulation used the same ingredients and manufacturing unit processes as the original formulation. The reformulated drug product was approved by the FDA on October 11, 2000 with an 18-month shelf-life. The shelf-life was extended to 36 months in an annual update to the FDA on December 1, 2005.

Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer.

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration's Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro-in vivo correlation considerations for transdermal systems.

Currently, bacterial conjunctivitis is managed by multiple antibiotic eye-drop solution, which is highly inefficient due to low ocular bioavailability and frequent dosing. Therapeutic soft contact lenses can be used to sustain the release of ocular drugs. However, the conventional soaking method (economic and widely used) showed low drug uptake and high burst release, and the optophysical properties of the contact lens were altered for clinical application. In this paper, novel ofloxacin-loaded niosomes were developed to increase the drug loading capacity of contact lenses while also sustaining ocular drug delivery. Ofloxacin-loaded niosomes were prepared by the thin film hydration technique with three levels of cholesterol. The niosome-laden contact lenses (OFL-Nio-L) led to improved optophysical properties (swelling, transmittance, oxygen permeability) and lysozyme adherence compared to the conventional soaked contact lens (CV-OFL-L). The in vitro drug release data of CV-OFL-L showed high burst release, while OFL-Nio-L lenses showed sustained release up to 48-96 h. In a rabbit tear fluid model, the OFL-Nio-100-L lens showed a high drug concentration at all-time points compared to the CV-OFL-L and eye-drop solution. The efficacy study in the rabbit model showed improved healing effect with OFL-Nio-100-L lens compared to frequent eye-drop therapy. In conclusion, the paper demonstrated the successful application of niosomes to deliver ofloxacin using contact lens without affecting the critical lens properties to substitute eye-drop therapy.

This work describes the lyophilization process validation and consists of two parts. Part one (Part I: Process Design and Modeling) focuses on the process design and is described in the previous paper, while the current paper is devoted to process qualification and continued process verification. The goal of the study is to show the cutting edge of lyophilization validation based on the integrated community-based opinion and the industrial perspective. This study presents best practices for batch size determination and includes the effect of batch size on drying time, process parameters selection strategies, and batch size overage to compensate for losses during production. It also includes sampling strategies to demonstrate batch uniformity as well as the use of statistical models to ensure adequate sampling. Based on the LyoHUB member organizations survey, the best practices in determining the number of PPQ runs are developed including the bracketing approach with minimum and maximum loads. Standard practice around CQA and CPP selection is outlined and shows the advantages of using control charts and run charts for process trending and quality control. The case studies demonstrating the validation strategy for monoclonal antibody and the impact of the loading process on the lyophilization cycle and product quality as well as the special case of lyophilization for dual-chamber cartridge system are chosen to illustrate the process validation. The standard practices in the validation of the lyophilization process, special lyophilization processes, and their impact on the validation strategy are discussed. Graphical Abstract

Currently, bacterial conjunctivitis is managed by multiple antibiotic eye-drop solution, which is highly inefficient due to low ocular bioavailability and frequent dosing. Therapeutic soft contact lenses can be used to sustain the release of ocular drugs. However, the conventional soaking method (economic and widely used) showed low drug uptake and high burst release, and the optophysical properties of the contact lens were altered for clinical application. In this paper, novel ofloxacin-loaded niosomes were developed to increase the drug loading capacity of contact lenses while also sustaining ocular drug delivery. Ofloxacin-loaded niosomes were prepared by the thin film hydration technique with three levels of cholesterol. The niosome-laden contact lenses (OFL-Nio-L) led to improved optophysical properties (swelling, transmittance, oxygen permeability) and lysozyme adherence compared to the conventional soaked contact lens (CV-OFL-L). The in vitro drug release data of CV-OFL-L showed high burst release, while OFL-Nio-L lenses showed sustained release up to 48-96 h. In a rabbit tear fluid model, the OFL-Nio-100-L lens showed a high drug concentration at all-time points compared to the CV-OFL-L and eye-drop solution. The efficacy study in the rabbit model showed improved healing effect with OFL-Nio-100-L lens compared to frequent eye-drop therapy. In conclusion, the paper demonstrated the successful application of niosomes to deliver ofloxacin using contact lens without affecting the critical lens properties to substitute eye-drop therapy.

This paper is a companion article to the research originally presented in "Estimating Shelf Life through Tolerance Intervals" (Schwenke et al., 21:290, 2020) published in AAPS PharmSciTech where tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research.

Abstract This work describes lyophilization process validation and consists of two parts. Part I focuses on the process design and is described in the current paper, while part II is devoted to process qualification and continued process verification. The intent of these articles is to provide readers with recent updates on lyophilization validation in the light of community-based combined opinion on the process and reflect the industrial prospective. In this paper, the design space approach for process design is described in details, and examples from practice are provided. The approach shows the relationship between the process inputs; it is based on first principles and gives a thorough scientific understanding of process and product. The lyophilization process modeling and scale-up are also presented showing the impact of facility, equipment, and vial heat transfer coefficient. The case studies demonstrating the effect of batch sizes, fill volume, and dose strength to show the importance of modeling as well as the effect of controlled nucleation on product resistance are discussed. Graphical abstract

Scale-up and transfer of lyophilization processes remain very challenging tasks considering the technical challenges and the high cost of the process itself. The challenges in scale-up and transfer were discussed in the first part of this paper and include vial breakage during freezing at commercial scale, cake resistance differences between scales, impact of differences in refrigeration capacities, and geometry on the performance of dryers. The second part of this work discusses successful and unsuccessful practices in scale-up and transfer based on the experience of the authors. Regulatory aspects of scale-up and transfer of lyophilization processes were also outlined including a topic on the equivalency of dryers. Based on an analysis of challenges and a summary of best practices, recommendations on scale-up and transfer of lyophilization processes are given including projections on future directions in this area of the freeze drying field. Recommendations on the choice of residual vacuum in the vials were also provided for a wide range of vial capacities. Graphical Abstract

Drug nanocrystals have been used for a wide range of drug delivery platforms in the pharmaceutical industry, especially for bioavailability enhancement of poorly water-soluble drugs. Wet stirred media milling (WSMM) is the most widely used process for producing dense, stable suspensions of drug nanoparticles, also referred to as nanosuspensions. Despite a plethora of review papers on the production and applications of drug nanosuspensions, modeling of WSMM has not been thoroughly covered in any review paper before. The aim of this review paper is to briefly expose the pharmaceutical scientists and engineers to various modeling approaches, mostly mechanistic, including computational fluid dynamics (CFD), discrete element method (DEM), population balance modeling (PBM), coupled methods, the stress intensity-number model (SI-SN model), and the microhydrodynamic (MHD) model with a main focus on the MHD model for studying the WSMM process. A total of 71 studies, 30 on drugs and 41 on other materials, were reviewed. Analysis of the pharmaceutics literature reveals that WSMM modeling is largely based on empirical, statistically based modeling approaches, and mechanistic modeling could help pharmaceutical engineers develop a fundamental process understanding. After a review of the salient features and various pros-cons of each modeling approach, recent advances in microhydrodynamic modeling and process insights gained therefrom were highlighted. The SI-SN and MHD models were analyzed and critiqued objectively. Finally, the review points out potential research directions such as more mechanistic and accurate CFD-DEM-PBM simulations and the coupling of the MHD-PBM models with the CFD.

Bimatoprost is widely used for the management of glaucoma. Currently, it is delivered via eye drop solution, which is highly inefficient due to low bioavailability. To control the release of ocular drugs, contact lenses are used by scientists. However, the conventional soaking method showed high burst release due to absence of any efficient controlling membrane. The objective of the paper was to apply molecular imprinting technology to improve the loading of bimatoprost from the soaking solution and to sustain the release of drug from the contact lens. The bimatoprost was loaded by conventional soaking method (BT-SM) and compared with the molecular imprinted contact lenses (BT-MP). The loading of bimatoprost by molecular imprinting technology affect the swelling of the contact lens; however, the batch BT-MP-10 did not showed significant alterations. The uptake study showed improvement in the bimatoprost loading by molecular imprinting technology in comparison to the conventional soaking technology. The in vitro bimatoprost release data showed improvement in the bimatoprost release rate profiles with BT-MP contact lenses (up to 36–60 h) lenses in comparison to BT-SM contact lenses (up to 24–36 h). The in vivo rabbit tear fluid data with BT-MP batch showed improvement in the bimatoprost retention time in comparison to BT-SM contact lens and eye drop solution. The rabbit model failed to respond bimatoprost; thus, the efficacy studies need to be conducted on canines or human primates. The paper revealed the potential of using molecular imprinting technology to improve the uptake of bimatoprost and to achieve sustain release kinetics without altering the swelling, transmittance and folding endurance properties of the contact lens.

This paper describes a pragmatic approach that can be applied in assessing powder blend and unit dosage uniformity of solid dose products at Process Design, Process Performance Qualification, and Continued/Ongoing Process Verification stages of the Process Validation lifecycle. The statistically based sampling, testing, and assessment plan was developed due to the withdrawal of the FDA draft guidance for industry "Powder Blends and Finished Dosage Units-Stratified In-Process Dosage Unit Sampling and Assessment." This paper compares the proposed Grouped Area Variance Estimate (GAVE) method with an alternate approach outlining the practicality and statistical rationalization using traditional sampling and analytical methods. The approach is designed to fit solid dose processes assuring high statistical confidence in both powder blend uniformity and dosage unit uniformity during all three stages of the lifecycle complying with ASTM standards as recommended by the US FDA.

For progression of health care system, it has always been a challenge to the researchers for formulation to a type of advanced drug delivery system which will have less toxicity, targeted delivery and will be highly biodegradable. Nano science or nanotechnology has been validated to be a successful method as of targeting the drug to its active site be due to its special physicochemical properties and size thereby reducing the dose of administration, increasing bioavailability, and also reducing toxicity. Magnetic nanoparticles recently in few decades have proved as an effective advanced drug delivery system for its elevated magnetic responsiveness, biocompatibility, elevated targeted drug delivery effectiveness, etc. The drug can be easily targeted to active site by application of external magnetic field. Among the various elements, nanoparticles prepared with magnetically active iron oxide or other iron-based spinel oxide nanoparticles are widely used due to its high electrical resistivity, mechanical hardness, chemical stability, etc. Owing to their easy execution towards drug delivery application, extensive research has been carried out in this area. This review paper has summarized all recent modifications of iron-based magnetically active nanoparticle based drug delivery system along with their synthesis, characterization, and applications.

The freeze-drying process scale-up and transfer remain a complicated and non-uniform practice. We summarized inefficient and good practices in these papers and provided some practical advice. It was demonstrated that using the same process set points/times in laboratory and commercial scale dryers may lead to loss of product quality (collapse or vial breakage). The emerging modeling approach demonstrated practical advantages. However, the upfront generation of some input parameters (vial heat transfer coefficient, minimum controllable pressure, and maximum sublimation rate) is essential for model utilization. While the primary drying step can be transferred with a high degree of confidence (e.g., using modeling), and secondary drying is usually fairly straightforward, predicting potential changes in product behavior during freezing remains challenging. Graphical Abstract

Bimatoprost is widely used for the management of glaucoma. Currently, it is delivered via eye drop solution, which is highly inefficient due to low bioavailability. To control the release of ocular drugs, contact lenses are used by scientists. However, the conventional soaking method showed high burst release due to absence of any efficient controlling membrane. The objective of the paper was to apply molecular imprinting technology to improve the loading of bimatoprost from the soaking solution and to sustain the release of drug from the contact lens. The bimatoprost was loaded by conventional soaking method (BT-SM) and compared with the molecular imprinted contact lenses (BT-MP). The loading of bimatoprost by molecular imprinting technology affect the swelling of the contact lens; however, the batch BT-MP-10 did not showed significant alterations. The uptake study showed improvement in the bimatoprost loading by molecular imprinting technology in comparison to the conventional soaking technology. The in vitro bimatoprost release data showed improvement in the bimatoprost release rate profiles with BT-MP contact lenses (up to 36-60 h) lenses in comparison to BT-SM contact lenses (up to 24-36 h). The in vivo rabbit tear fluid data with BT-MP batch showed improvement in the bimatoprost retention time in comparison to BT-SM contact lens and eye drop solution. The rabbit model failed to respond bimatoprost; thus, the efficacy studies need to be conducted on canines or human primates. The paper revealed the potential of using molecular imprinting technology to improve the uptake of bimatoprost and to achieve sustain release kinetics without altering the swelling, transmittance and folding endurance properties of the contact lens.

An integrated approach based on QbD and PAT provides a systematic and innovative framework for product development, manufacturing, and quality risk management. In this context, the significance of the outcome of design of experiments (DOEs) to the selection of the product design, robust commercial manufacturing process, design space, and overall control strategy remains vital for the success of a drug product throughout its life cycle. This paper aims at discussing selected recent DOE case studies conducted during QbD-based and integrated QbD/PAT-based development of solid oral formulations and process improvement studies. The main focus of this paper is to highlight the rationales and importance of design selection during development and applications of mathematical models and statistical tools in analyzing DOE and PAT data for developing a design space, control strategy, and improved process monitoring. A total of 25 case studies (includes 9 PAT application studies) have been discussed in this paper which cover 11 manufacturing processes commonly utilized for solid dosage forms. Two case studies relevant to selection of packaging design for solid dosage forms are also briefly discussed to complete the scope. Overall, for a successful modern QbD approach, it is highly important that DOEs are conducted and analyzed in a logical sequence which involves designs that are phase-appropriate and quality-driven and facilitate both statistical and chemometric thinking at each development stage. This approach can result into higher regulatory flexibility along with lower economic burden during life cycle of a product, irrespective of regulatory path used (NDA or ANDA).

Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p ≤ 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results—RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators. Graphical abstract

Microparticulate drug delivery systems, e.g., micropellets (MPs), are used in a variety of pharmaceutical formulations such as suspensions, injectable systems, and capsules. MPs are currently manufactured mainly via batch, solvent-based processes, e.g., spray-drying and solvent evaporation-extraction. In this paper, we present a novel, solvent-free, continuous hot-melt extrusion-based approach with an inline cold pelletization step and the potential of unprecedented on-the-fly formulation changes, aiming at producing the smallest particles usable for injectable applications. A biodegradable, crystalline dispersion consisting of poly(DL-lactic acid) (PLA) filled with metformin as the model drug was chosen on purpose to elucidate the broad applicability of the process also to formulations with limited stretchability and complex pelletizability. Next to optical/statistical particle analyses and in-line high-speed camera investigations providing insights into the pelletization process, the injectability of the most promising micropellets was compared to that of one marketed formulation. Fast extrudate haul-off speeds and high numbers of pelletizer knives resulted in particles with a narrow and small particle size distribution with a d

In our previous paper, we demonstrated the ex vivo studies of non-toxic liposome-nanogel systems by which the long-term drug release could be provided from hybrid systems for the 5-fluorouracil (5-FU) drug molecule. The aim of this study was the in vivo magnetic targeting of 5-FU-loaded Fe

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.

Palatability and swallowability in the pediatric population are perceived as true challenges in the oral administration of medication. Pediatric patients have high sensitivity to taste and reduced ability to take solid dosage forms, which can often lead to a poor therapeutic compliance. It is crucial to find new strategies to simplify the oral administration of drugs to children. The present paper reports the development of a new hydrogel vehicle adapted to the pediatric population. Several polymers with similar properties were selected and adjustments were made to obtain the desired characteristics of the final product. The developed formulations were studied for organoleptic properties, rheology, mucoadhesion properties, preservative efficacy, and stability. Physical and chemical compatibilities between the vehicle and several drugs/medicines, at the time of administration, were also studied. Six final formulations with different polymers, odor, and color were chosen, and no known interactions with medications were observed. The proposed new oral vehicles are the first sugar-free vehicle hydrogels designed to make the intake of oral solid forms a more pleasant and safer experience for pediatric patients., This research was funded by FCT (Fundação para a Ciência e a Tecnologia) through iMed.ULisboa UID/DTP/04138/2020 and UIDB/04138/2020). Joana Marto is financed through FCT, I.P., under the Scientific Employment Stimulus—Institutional Call (CEECINST/00145/2018).

Monoclonal antibodies (mAbs), while incredibly successful, are prone to a variety of degradation pathways, the most significant of which is aggregation. One of the most commonly used strategy to overcome protein aggregation is addition of excipients to the formulation. Osmolytes such as trehalose, sucrose, and glycine are widely used. In this paper, we explore potential use of naturally occurring osmolytes such as betaine, sarcosine, ectoine, and hydroxyectoine for reducing aggregation of mAb therapeutics. Experimentation has been performed on two IgG1 mAbs via accelerated stability studies. A variety of analytical tools have been used for monitoring the impact, dynamic light scattering (DLS) for colloidal stability, Fourier transform infrared (FTIR) spectroscopy and fluorescence spectroscopy for conformational stability and the higher order structure (HOS), and differential scanning calorimetry (DSC) for thermal stability. No significant impact of osmolyte addition was observed on protein structure, on comparative Fc receptor (FcRn) binding, and on biocompatibility as per our hemolytic assay. Our results rank the osmolytes’ stabilizing trend to be sarcosine > betaine > hydroxyectoine > ectoine. Sarcosine emerged as the most successful osmolyte rendering highest degree of protection against aggregation. Our data support the prospect of using these osmolytes as successful excipients for mAb formulations. Supplementary Information The online version contains supplementary material available at 10.1208/s12249-021-02183-8.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle

In the advancement of tumor therapy, in addition to the search for new antitumor compounds, the development of nano-drug delivery systems has opened up new pathways for tumor treatment by addressing some of the limitations of traditional drugs. Liposomes have received much attention for their high biocompatibility, low toxicity, high inclusivity, and improved drug bioavailability. They are one of the most studied nanocarriers, changing the size and surface characteristics of liposomes to better fit the tumor environment by taking advantage of the unique pathophysiology of tumors. They can also be designed as tumor targeting drug delivery vehicles for the precise delivery of active drugs into tumor cells. This paper reviews the current development of liposome formulations, summarizes the characterization methods of liposomes, and proposes strategies to improve the effectiveness of tumor treatment. Finally, it provides an outlook on the challenges and future directions of the field. Graphical abstract.

Currently, glaucoma is managed by frequent instillation of bimatoprost eye drop therapy, which showed very poor ocular bioavailability. Contact lens is widely used as medical device to improve the drug retention on the ocular tissues. However, the traditional methods of drug loading in the contact lens matrix showed high burst release and changes the optophysical properties of the contact lens material. In this paper, a novel bimatoprost-loaded silica shell nanoparticles-laden soft contact lenses were developed to achieve sustain drug delivery without altering the optophysical properties of the contact lens. Silica-shell nanoparticles were prepared using octyltrimethoxysilane (OTMS) and microemulsion. Traditional soaking method (SM-BT), direct bimatoprost loading method (DL-BT), and microemulsion-laden contact lens (ME-BT) were developed for comparison. The silica shell-coated nanoparticles-laden soft contact lenses (SiS-BT) showed improved swelling, transmittance, oxygen permeability, and lysozyme adherence compared to SM-BT, DL-BT, and ME-BT lenses. The DL-BT and ME-BT batch showed high bimatoprost lost/leaching during extraction and sterilization steps, with low cumulative drug release. Also, SiS-BT lens showed sustain bimatoprost release for 96 h. In a rabbit tear fluid model, the SiS-BT lens showed high bimatoprost concentration for 72 h compared to ME-BT lens and eye drop therapy. Based on histopathological studies of cornea, the SiS-BT lens was found to be safe for human applications. The data demonstrated the novel application of silica shell nanoparticles to deliver bimatoprost from the contact lens for extended period of time without altering the optophysical properties of the contact lens.

The purpose of this paper is to prepare a stable apigenin nanosuspension with a drug concentration of 1.11 mg/mL through green and efficient antisolvent method. Compared with the traditional preparation process that may use toxic reagents, in this study, a green and effective strategy was applied for the preparation of stable apigenin nanosuspension by using an antisolvent method with PEG 400 as antisolvent to improve the solubility and bioavailability. It was found that the particle size of apigenin nanosuspension was about 280 nm, and the solubility and dissolution of the nanosuspension were 33 and 3 times higher than that of the apigenin, respectively. Pharmacokinetic study showed that the C

In order to better explain and predict the dissolution characteristics of binary drug delivery systems (BDDSs), the dissolution behaviors of co-crystal (CC) and co-amorphous (CA) systems of sacubitril (SCB) and valsartan (VST) were evaluated in vitro and in vivo by thermodynamic and kinetic methods. The CCs of SCB and VST were prepared into a CA state through rotary evaporation. Solid-state properties were systematically evaluated. Herein, based on the results from previous studies of single-phase systems, we used thermodynamic methods to evaluate the increase in drug dissolution rate after BDDSs change from the crystalline to the amorphous state. After comparing the predicted and measured dissolution rate enhancement of the CC and CA systems, this paper attempts to explain the dissolution rate characteristics of the BDDSs. We then evaluated the bioavailability of two BDDSs in beagle dogs to confirm that there was no discrepancy in vivo with the results obtained in vitro. The results exhibited that there is strong intermolecular interaction between SCB and VST and good physical stability for the CA system. Compared with the CC, the bioavailability of SCB and VST in the CA system increased by 313.9% and 130.5%, respectively. The predicted dissolution rate ratio between CC and CA systems and their actual intrinsic dissolution rates differed by only a factor of 2.5, demonstrating the good correlation between the predicted and measured values. In the future, this method could be expanded to a variety of new samples and exciting drug prospects.

This paper reports for the first time the possible formation of a novel room temperature therapeutic deep eutectic solvent (THEDES) of risperidone (RIS) with some fatty acids, namely capric acid (C10; CA), lauric acid (C12; LA), and myristic acid (C14; MA). All mixtures of RIS and MA yielded a solid or pasty-like solid and were readily discarded. Some of the prepared THEDESs from RIS and CA or LA have spontaneously transformed into a transparent liquid, without any precipitate at room temperature by simple physical mixing of the components. From the DSC thermograms, phase diagrams of the eutectic systems were constructed and the lowest obtained melting point for a RIS:CA mixture was 17°C at 40:60% w/w ratio. While 22°C was recorded as the lowest melting point for RIS:LA at a ratio of 30:70% w/w, solubility improvement of RIS was up to 70,000-fold compared with water. Freeze-drying microscopy provided valuable information regarding the phase change and transitions the drug undergoes as a function of temperature and it clarifies the interpretation of the DSC results and provides valuable evidence of drug crystals co-melting within the fatty acid base. The presence of natural fatty acid as one component of THEDES and the depression in the melting point significantly (P

Solid dispersion is the preferred technology to prepare efficacious forms of BCS class-II/IV APIs. To prepare solid dispersions, there exist a wide variety of polymeric carriers with interesting physicochemical and thermochemical characteristics available at the disposal of a formulation scientist. Since the advent of the solid dispersion technology in the early 1960s, there have been more than 5000 scientific papers published in the subject area. This review discusses the polymeric carrier properties of most extensively used polymers PVP, Copovidone, PEG, HPMC, HPMCAS, and Soluplus® in the solid dispersion technology. The literature trends about preparation techniques, dissolution, and stability improvement are analyzed from the Scopus® database to enable a formulator to make an informed choice of polymeric carrier. The stability and extent of dissolution improvement are largely dependent upon the type of polymeric carrier employed to formulate solid dispersions. With the increasing acceptance of transfer dissolution setup in the research community, it is required to evaluate the crystallization/precipitation inhibition potential of polymers under dynamic pH shift conditions. Further, there is a need to develop a regulatory framework which provides definition and complete classification along with necessarily recommended studies to characterize and evaluate solid dispersions. Supplementary Information The online version contains supplementary material available at 10.1208/s12249-020-01849-z.

Experimental studies have reported the fundamental and applied science aspects of polyelectrolyte (PE) layer-by-layer (LbL) self-assembly. LbL nanocoating is a simple and robust technique that can be used to modify the surface properties of nearly any material. These modifications take place by adsorption of mere nanometers of PE to impart previously absent properties to the nanocoated substrate. Paper manufacturing, drug delivery, and antimicrobial applications have since been developed. LbL self-assembly has become a very lucrative field of research. Computational modeling of LbL nanocoating has received limited attention. PE simulations often require significant computational resources and make computational modeling studies challenging. In this study, atomic-level PE and dexamethasone models are developed and then converted into coarse-grained (CG) models. This modeling study is based on experimental results that were previously reported. The CG models showed the effect of salt concentration and the number of PE layers on the LbL drug nanocapsule. The suitability of the model was evaluated and showed that this model can serve as a predictive tool for an LbL-nanocoated drug delivery system. It is suggested that this model can be used to simulate LbL drug delivery systems before the experimental evaluation of the real systems take place.

This paper is a continuation of the research published by the Stability Shelf Life Working Group as chartered under the Product Quality Research Institute. The Working Group was formed in 2006 and disbanded in late 2019. Following the philosophy presented by the Working Group on how to characterize the stability shelf life paradigm (Capen et al., 2012), shelf life is estimated here in terms of defining risk as a specified proportion of the pharmaceutical stability distribution of interest being out of specification. Shelf life can be defined for the batch mean distribution for regulatory issues, as well as for the product distributions for patient interests. Estimates of shelf life are proposed corresponding to each stability distribution through the use of statistical tolerance intervals. Appropriate estimates of the between-batch and within-batch variance components are obtained through a random coefficient mixed regression model analysis based on the best fit to batch stability response data. Tolerance interval estimates are computed as part of the mixed model analysis and computed directly using the statistical definition of the stability distributions. A proposed rationale is offered on how to select an appropriate proportion allowed out of specification to define a meaningful shelf life. Examples of the proposed shelf life estimates are presented using industry stability batch data. For each example, the traditional ICH shelf life estimate is given for comparison.

Polyvinylpyrrolidone (PVP), a non-ionic polymer, has been employed in multifarious fields such as paper, fibers and textiles, ceramics, and pharmaceutics due to its superior properties. Especially in pharmacy, the properties of inertness, non-toxicity, and biocompatibility make it a versatile excipient for both conventional formulations and novel controlled or targeted delivery systems, serving as a binder, coating agent, suspending agent, pore-former, solubilizer, stabilizer, etc. PVP with different molecular weights (MWs) and concentrations is used in a variety of formulations for different purposes. In this review, PVP-related researches mainly in recent 10 years were collected, and its main pharmaceutical applications were summarized as follows: (i) improving the bioavailability and stability of drugs, (ii) improving the physicomechanical properties of preparations, (iii) adjusting the release rate of drugs, and (iv) prolonging the in vivo circulation time of liposomes. Most of these applications could be explained by the viscosity, solubility, hydrophilicity, and hydrogen bond-forming ability of PVP, and the specific action mechanisms for each application were also tried to figure out. The effect of PVP on bioavailability improvement establishes it as a promising polymer in the emerging controlled or targeted formulations, attracting growing interest on it. Therefore, given its irreplaceability and tremendous opportunities for future developments, this review aims to provide an informative reference about current roles of PVP in pharmacy for interested readers.

After the Food and Drug Association in the USA published guidelines on the enhanced use of process analytical technology (PAT) and continuous manufacturing, many studies regarding PAT and continuous manufacturing have been published. This paper describes a case study involving granulation and coating steps with ethenzamide to investigate interference for PAT model construction and model management. We investigated what factors should be considered and addressed when PAT is implemented for continuous manufacturing and how predictive models should be constructed. The product qualities that were monitored were moisture content and particle size in the granulation step and tablet weight and moisture content in the coating step. We have constructed models for the granulation step and validated the predictive capability of the models against an external dataset. A partial least squares (PLS) model with manual wavelength selection had the best predictive accuracy for loss on drying against the external validation set. We found that the prediction of loss on drying was accurate, but the prediction of particle size was not sufficiently accurate. In the coating step, because of the small amount of data, we performed three-fold cross-validation and y-scrambling 10 times, to select the optimal hyper-parameters and to check if the models were fitted to chance correlations. We confirmed that the coating agent weights, tablet weights, and water content could be accurately predicted based on the mean of the R2 score for cross-validation. Addition of other variables, as well as the absorbance, slightly improved the predictive accuracy.

In 2017, there are 451 million people with diabetes worldwide. These figures were expected to increase to 693 million by 2045. The research and development of hypoglycemic drugs has become a top priority. Among them, sulfonylurea hypoglycemic drugs such as glipizide are commonly used in non-insulin-dependent type II diabetes. In order to adapt to the wide range of hypoglycemic drugs and the different individual needs of patients, this topic used glipizide as a model drug, and prepared glipizide preparations with 3D printing technology. The purpose of this study was to investigate the prescription applicability and control-release behavior of structure and explore the application prospects of 3D printing personalized drug delivery formulations. This article aims to establish a production process for personalized preparations based on 3D printing technology. The process is easy to obtain excipients, universal prescriptions, flexible dosages, exclusive customization, and integrated automation. In this paper, the UV method was used to determine the in vitro release and content analysis method of glipizide; the physical and chemical properties of the glipizide were investigated. The established analysis method was inspected and evaluated, and the experimental results met the methodological requirements. Glipizide controlled-release tablets were prepared by the semisolid extrusion (SSE) method using traditional pharmaceutical excipients combined with 3D printing technology. The formulation composition, in vitro release, and printing process parameters of the preparation were investigated, and the final prescription and process parameters (traveling speed 6.0–7.7 mm/s and extruding speed 0.0060–0.0077 mm/s) were selected through comprehensive analysis. The routine analysis results of the preparation showed that the performance of the preparation meets the requirements. In order for 3D printing technology to play a better role in community medicine and telemedicine, this article further explored the universality of the above prescription and determined the scope of application of prescription drugs and dosages. Glipizide, gliclazide, lornoxicam, puerarin, and theophylline were used as model drugs, and the range of drug loading percentage was investigated. The results showed when the solubility of the drug is 9.45 –8.34 mg/mL, and the drug loading is 3–43%; the release behavior is similar.

This paper presents a rational workflow for developing enabling formulations, such as amorphous solid dispersions, via hot-melt extrusion in less than a year. First, our approach to an integrated product and process development framework is described, including state-of-the-art theoretical concepts, modeling, and experimental characterization described in the literature and developed by us. Next, lab-scale extruder setups are designed (processing conditions and screw design) based on a rational, model-based framework that takes into account the thermal load required, the mixing capabilities, and the thermo-mechanical degradation. The predicted optimal process setup can be validated quickly in the pilot plant. Lastly, a transfer of the process to any GMP-certified manufacturing site can be performed in silico for any extruder based on our validated computational framework. In summary, the proposed workflow massively reduces the risk in product and process development and shortens the drug-to-market time for enabling formulations.

Niacin (nicotinic acid, NA) is administered orally as an antihyperlipidemic agent in extended-release (ER) tablets in high doses. Due to rapid absorption and extensive metabolism (non-linear pharmacokinetics), the drug plasma levels are highly variable, which may correlate with side effects. Interestingly, this erratic drug delivery behavior of niacin ER products cannot be clarified by compendial in vitro release testing. The standard dissolution tests do not allow to mimic the selected GI tract characteristics in order to estimate the robustness of formulation under the variability of the physiological conditions. These are characterized by the pH value, impact of motility forces and composition, as well as volume of GI liquids. Our paper demonstrates a comparison of a newly developed ER HPMC niacin formulation with an originator product. The research aimed to design a robust matrix tablet of comparable biopharmaceutical behavior, safety and efficacy. The extensive in vitro investigation, including dynamic studies in flow-through cell apparatus and stress test device, forms the basis for the evaluation of nicotinic acid plasma concentrations in vivo. The occurrence of erratic, multiple NA plasma peaks after the administration of both extended-release products is a result of its local input excess over the metabolic threshold (at the level corresponding to maximum 2% of the administered dose, i.e., 20 mg of drug) due to the mechanical stresses of physiological intensity. We demonstrate how this behavior is similar for both marketed and test products. In this context, we describe how a robust ER matrix and well-designed formulation does not guarantee the test product’s bioequivalence to the comparator one out of reasons unrelated to technology and biopharmaceutical properties, but because of the active compound’s intrinsic pharmacokinetic characteristics, i.e., highly variable, extensive metabolism of nicotinic acid. Electronic supplementary material The online version of this article (10.1208/s12249-019-1600-z) contains supplementary material, which is available to authorized users.

A heightened interest in (trans)dermal delivery is in part driven by the need to improve the existing skin therapies and also the demand for alternative routes of administration, notably for pharmaceutical actives with undesirable oral absorption characteristics. The premise of delivering difficult actives to the skin or via the skin however is weighed down by the barrier function properties of the stratum corneum. Short of disrupting the skin by physical means, scientists have resorted to formulation with excipients known to enhance the skin penetration and permeation of drugs. A vehicle that has emerged over the years as a safe solubilizer and enhancer for a broad range of drug actives is the highly purified NF/EP grade of diethylene glycol monoethyl ether (DEGEE) commercially known as Transcutol®. Whereas numerous studies affirm its enhancing effect on drug solubilization, percutaneous absorption rate, and/or drug retention in the skin, there are few publications that unite the body of the published literature in describing the precise role and mechanisms of action for Transcutol®. In view of the current mechanistic understanding of skin barrier properties, this paper takes on a retrospective review of the published works and critically evaluates the data for potential misses due to experimental variables such as formulation design, skin model, skin hydration levels, and drug properties. The goal of this review is to mitigate the incongruence of the published works and to construct a unified, comprehensive understanding of how Transcutol® influences skin penetration and permeation. Graphical Abstract Transcutol has affinity for the hydrophilic head groups of the stratum corneum structures.

One of the current methods for cycle optimization in primary drying to is develop a graphical design space based on quality by design (QbD). In order to construct the design space, the vial heat transfer coefficient (Kv) is needed. This paper investigated experimental factors that can affect the Kv result, examined the relationship between the batch average Kv and Kv values for individual vials, and recommended best practices for measuring Kv. Factors investigated included the technique for measuring ice temperature, shelf temperature, the use of a radiation shield on the door of the freeze-dry chamber, and shelf spacing. All experiments reported here used a chamber pressure of 100 mTorr. The most important factor was the technique for ice temperature measurement, where it is important to assure that any restrictions to vapor flow at the top of the vial are the same between monitored and non-monitored vials. Another factor that was found to play a role was the shelf temperature whereby the lower the shelf temperature, the larger the "edge effect," and the larger the average Kv. Factors that were found to not have a significant effect were the use of a radiation shield inside the chamber door and the shelf spacing. Being aware of these factors and knowing best practices when determining the vial heat coefficient will lead to more accurate design spaces and better cycle optimization.

This paper focuses on the development and evaluation of mucoadhesive vaginal gel of fluconazole using nanolipid carriers to enhance tissue deposition in treating vulvovaginal candidiasis. Treatment of vulvovaginal candidiasis includes antimycotic agents prescribed for 1 to 7 days or longer, in relapse either orally or topically. The delivery of fluconazole as nanolipid carriers in vaginal gel can be proposed as suitable alternative to the existing conventional formulations to improve the patient acceptability, compliance and localized drug action. The nanolipid carriers of fluconazole were prepared by phase inversion temperature technique and incorporated into Carbopol 974P as gelling polymer. GRAS excipients selected and optimized were Precirol ATO 5, oleic acid and Kolliphor RH 40 to produce nanolipid dispersions. Stable nanolipid dispersions were developed using sodium dodecyl sulfate as the charge inducer. The optimized nanolipid dispersion of fluconazole had particle size, polydispersity index and zeta potential value of 158.33 ± 2.55 nm, 0.278 ± 0.003 and - 27.33 ± 0.40 mV, respectively and the average entrapment of fluconazole in the lipid carriers was found to be 67.24 ± 0.87%. The optimized vaginal gel had satisfactory mucoadhesive strength and rheological properties to facilitate vaginal application. The fluconazole release from the gel was sustained showing 30.69 ± 1.02% drug deposition in the porcine vaginal mucosa at the end of 8 h with improved antifungal activity against Candida albicans during well diffusion studies. The optimized gel was non-irritant to the vaginal mucosa of female Wistar rats with no signs of erythema or edema.

Qualitative risk assessment methods are often used as the first step to determining design space boundaries; however, quantitative assessments of risk with respect to the design space, i.e., calculating the probability of failure for a given severity, are needed to fully characterize design space boundaries. Quantitative risk assessment methods in design and operational spaces are a significant aid to evaluating proposed design space boundaries. The goal of this paper is to demonstrate a relatively simple strategy for design space definition using a simplified Bayesian Monte Carlo simulation. This paper builds on a previous paper that used failure mode and effects analysis (FMEA) qualitative risk assessment and Plackett-Burman design of experiments to identity the critical quality attributes. The results show that the sequential use of qualitative and quantitative risk assessments can focus the design of experiments on a reduced set of critical material and process parameters that determine a robust design space under conditions of limited laboratory experimentation. This approach provides a strategy by which the degree of risk associated with each known parameter can be calculated and allocates resources in a manner that manages risk to an acceptable level.