Development of Losartan Orally Disintegrating Tablets by Direct Compression: a Cost-Effective Approach to Improve Paediatric Patient's Compliance.

The development of suitable dosage forms is essential for an effective pharmacological treatment in children. Orally disintegrating tablets (ODTs) are attractive dosage forms that avoid swallowing problems, ensure dosage accuracy and are easy to administer as they disintegrate in the oral cavity. This study aimed to develop ODTs containing losartan potassium (LP) for the treatment of arterial hypertension in children. The ODTs, produced by the cost-effective manufacturing process of direct compression, consisted of a mixture of diluent, superdisintegrant, glidant and lubricant. Five superdisintegrants (croscarmellose sodium, two grades of crospovidone, sodium starch glycolate and pregelatinized starch) were tested (at two concentrations), and combined with three diluents (mannitol, lactose and sorbitol). Thus, thirty formulations were evaluated based on disintegration time, hardness and friability. Two formulations, exhibiting the best results concerning disintegration time (< 30 s), hardness and friability (≤ 1.0%), were selected as the most promising ones for further evaluation. These ODTs presented favourable drug-excipient compatibility, tabletability and flow properties. The in vitro dissolution studies demonstrated 'very rapid' drug release. Preliminary stability studies highlighted the requirement of a protective packaging. All quality properties retained appropriate results after 12 months of storage in airtight containers. In conclusion, the ODTs were successfully developed and characterised, suggesting a potential means to accomplish a final prototype that enables an improvement in childhood arterial hypertension treatment.

Utilization of wollastonite, jarosite, and their blends for the sustainable development of concrete paver block mixes containing reclaimed asphalt pavement aggregates.

While several research studies considered the utilization of reclaimed asphalt pavement (RAP) aggregates for asphalt and concrete pavements, very few attempted its possible utilization for precast concrete applications like concrete paver blocks (CPBs). Moreover, few attempts made in the recent past to improve the strength properties of RAP inclusive concrete mixes by incorporating certain supplementary cementitious materials (SCMs) have reported an insignificant or marginal effect. The present study attempts to comprehensively investigate the utilization potential of some locally and abundantly available materials having suitable physicochemical properties to improve the performance of a zero-slump CPB mix containing 50% RAP aggregates. The studied filler materials, namely, wollastonite (naturally occurring calcium metasilicate mineral) and jarosite (hazardous zinc industry waste), were used to replace 5-15% and 10-20% by volume of Portland cement in the 50% RAP CPB mix. Apart from their individual effects, the efficacy of wollastonite-jarosite blends was also investigated. Considering the lack of indoor storage facilities and economic aspects of CPBs, the influence of water spray curing regime on the performance of the RAP CPB mixes was studied and compared to that of continuous water curing regime. Inclusion of the considered fillers was found to statistically and significantly enhance the flexural strength, tensile splitting strength, and abrasion resistance of the 50% RAP CPB mix; however, the compressive strength (in most cases), permeable voids, water absorption, and water permeability properties showed an insignificant improvement. Results of thermogravimetric analysis confirmed the occurrence of pozzolanic reactivity, and microstructure analysis revealed improvements in packing of concrete matrix and ITZ with filler inclusion qualitatively substantiating the improvements in strength and durability characteristics. The toxicity characteristics of heavy metals that may leach from the hazardous jarosite-based RAP CPB mixes were found to be within permissible limits. Based on the performance requirements specified by IS, IRC, and ASTM standards, all the RAP CPB mixes with filler inclusions fulfilled the acceptance criteria for heavy traffic applications, and water spray curing can enact as an alternate method for curing these mixes. However, to avail maximum performance benefits, it is recommended to use 5% wollastonite, 15% jarosite, and a combination of 10% wollastonite and 10% jarosite as a Portland cement substitute to produce sustainable eco-friendly RAP CPB mixes.

A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry.

Pharmaceutical products represent a meaningful target for sustainability improvement and emissions reduction. It is proposed here that rethinking the standard, and often linear, approach to the synthesis of Active Pharmaceutical Ingredients (API) and subsequent formulation and drug product processing will deliver transformational sustainability opportunities. The greatest potential arguably involves API that have challenging physico-chemical properties. These can require the addition of excipients that can significantly exceed the weight of the API in the final dosage unit, require multiple manufacturing steps to achieve materials amenable to delivering final dosage units, and need highly protective packaging for final product stability. Co-processed API are defined as materials generated via addition of non-covalently bonded, non-active components during drug substance manufacturing steps, differing from salts, solvates and co-crystals. They are an impactful example of provocative re-thinking of historical regulatory and quality precedents, blurring drug substance and drug product operations, with sustainability opportunities. Successful examples utilizing co-processed API can modify properties with use of less excipient, while simultaneously reducing processing requirements by delivering material amenable to continuous manufacturing. There are also opportunities for co-processed API to reduce the need for highly protective packaging. This commentary will detail the array of sustainability impacts that can be delivered, inclusive of business, regulatory, and quality considerations, with discussion on potential routes to more comprehensively commercialize co-processed API technologies.

Ultrasound assessment of the nose vasculature: A review of the common method of non-surgical filler-based rhinoplasty.

BACKGROUND: With the increasing use of dermal injectable fillers in aesthetic medicine, the popularity of non-surgical filler-based rhinoplasty (NSR) is also growing. While performing this procedure might result in certain vascular complications, injecting deep into the midline of the nose is commonly considered the safest method for blind primary NSR. AIMS: In this study, we challenged the common NSR method with a Doppler ultrasound study of the nose. PATIENTS/METHODS: The vascular pattern of the common zones of the NSR procedure (radix and nasal tip) of 21 Iranian women were investigated by using a 14 MHz Doppler handheld ultrasound device (Silarious L14PS). Participants had never undergone any procedure on their nose. We focused on the depth of midline vessels in the radix and nasal tip. The radix was studied sagittally and horizontally, and the nasal tip was examined axially by ultrasound. RESULTS: In the radix of eight cases (38%), at least one vessel was observed at midline, and all were superficial. In the nose tip of 18 cases (86%), at least one vessel was observed at midline, and 9 out of these 18 vessels (50%) were deep. As a result, conducting NSR by the common method in our study population was relatively safe in the radix, but there was an increased likelihood of vascular events in the tip. CONCLUSION: Our research results show that while the common method of the NSR may carry a high risk of vascular events, the safety of this procedure could be enhanced by using ultrasound for planning and conducting a tailored treatment.

Pharmaceutical Assessment of the Impact of the Method of Extraction on the Suitability of Pectin from Plantain (Musa paradisiaca) Peels as a Suspending Agent in Oral Liquid Formulations.

Natural polymers such as pectin have gained increased utilization in pharmaceutical and biotechnology sectors because they are affordable, easily accessible, nontoxic, and chemically modifiable, with the potential to be biodegradable and biocompatible. Musa paradisiaca (plantain) peels make up 30-40% of the overall weight of the fruit. The extraction of pectin from these residues can therefore be viewed as a possible waste of wealth. This study, therefore, focused on evaluating the suspending properties of pectin obtained from Musa paradisiaca (plantain) peels (through acid and alkaline extraction) and presented an alternative suspending agent in the pharmaceutical formulation of suspensions. The unripe peels of Musa paradisiaca were acquired and authenticated at the Department of Pharmacognosy, Faculty of Pharmacy and Pharmaceutical Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana. Pectin was extracted from the peels using both acid and alkaline extraction processes, respectively, characterized, and evaluated for its phytochemical properties. Different concentrations of the acid and alkaline pectin extracts were employed as a suspending agent in paracetamol suspensions, using acacia gum as a standard. The pectin yields obtained were 4.88% and 7.61% for the acid and alkaline extraction processes, respectively, while phytochemical screening revealed the presence of glycosides, tannins, saponins, and phenols in both extracts. The alkaline pectin extract recorded higher equivalent weight, degree of esterification, ash content, and crude content than the acid pectin extract, while FTIR identified similar functional groups in both acid and alkaline pectin extracts. The test suspensions reported significant differences (P < 0.05) in flow rates, ease of redispersion, sedimentation volumes, and rates compared with acacia gum. Moreover, when the acid and alkaline pectin extracts were compared, significant differences (P < 0.05) were observed in sedimentation rates and sedimentation volumes, suggesting that the extraction method may affect suspending properties. Ultimately, the alkaline pectin extract had better suspending properties than the acid pectin extract; however, they both can be used as an alternative to acacia gum as a suspending agent.

Can Pharmaceutical Excipients Threaten the Aquatic Environment? A Risk Assessment Based on the Microtox® Biotest.

The ecotoxicological impact of pharmaceuticals has received considerable attention, primarily focusing on active pharmaceutical ingredients (APIs) while largely neglecting the potential hazards posed by pharmaceutical excipients. Therefore, we analyzed the ecotoxicity of 16 commonly used pharmaceutical excipients, as well as 26 API-excipient and excipient-excipient mixtures utilizing the Microtox® test. In this way, we assessed the potential risks that pharmaceutical excipients, generally considered safe, might pose to the aquatic environment. We investigated both their individual ecotoxicity and their interactions with tablet ingredients using concentration addition (CA) and independent action (IA) models to shed light on the often-overlooked ecotoxicological consequences of these substances. The CA model gave a more accurate prediction of toxicity and should be recommended for modeling the toxicity of combinations of drugs with different effects. A challenge when studying the ecotoxicological impact of some pharmaceutical excipients is their poor water solubility, which hinders the use of standard aquatic ecotoxicity testing techniques. Therefore, we used a modification of the Microtox® Basic Solid Phase protocol developed for poorly soluble substances. The results obtained suggest the high toxicity of some excipients, i.e., SLS and meglumine, and confirm the occurrence of interactions between APIs and excipients. Through this research, we hope to foster a better understanding of the ecological impact of pharmaceutical excipients, prompting the development of risk assessment strategies within the pharmaceutical industry.

Assessment of the Water Sorption Capacity of Rifaximin Using the Dynamic Vapor Sorption Technique for Optimization of the Choice of Excipients and the Manufacturing Environment of Rifaximin Tablets.

BACKGROUND: Rifaximin, a medication of the rifamycin family with two distinct strengths of 200 mg and 550 mg in tablet form, is useful for the treatment of travelers' diarrhea. It has a solid yellow hue and is very hygroscopic in nature. It exhibits a variety of polymorphic forms such as α, ß, γ, δ, and ε depending on bonded moisture. These polymorphs' varying chemical and physical characteristics, such as solubility and water content, may have a big impact on in vivo absorption, which in turn affects efficacy and safety. Therefore, understanding the polymorphic stability of rifaximin is crucial for formulating rifaximin tablets. OBJECTIVE: The current effort focuses on the understanding of water vapor sorption properties to control the polymorphic stability of rifaximin in the tablet formulation using the appropriate selection of excipients and manufacturing process. METHODS: The dynamic vapor sorption method in the range of 0-90% relative humidity at 25°C is used for understanding the sorption properties of drug substances and drug excipient mixtures; the state-of-the-art techniques of the X-ray diffraction method are used to identify polymorph conversions; and dissolution procedures are used for in vitro correlation studies. RESULTS: The sorption study data reveals that rifaximin is highly unstable at relative humidity conditions above 36%. When using excipients that have a low tendency to adsorb water in the formulation, the polymorphic results do not show any change in their intended form, and the in vitro dissolution data show an equivalency with the reference drug product. CONCLUSION: The study prompted a successful outcome-oriented development of the formulation processing environment conditions design to develop a test formulation that has adequate polymorphic stability and also similarity in in-vitro dissolution profiles, with the reference product with highest similarity. HIGHLIGHTS: The overall study described here is useful for swiftly gaining insight into the sorption characteristics of rifaximin, and it contributes to the widespread acceptance of rifaximin tablets as a treatment option.

Manufacturing pharmaceutical mini-tablets for pediatric patients using drop-on-demand printing.

The pharmaceutical industry has traditionally manufactured medicines in a limited range of dose strengths, with an emphasis on addressing the needs of the largest patient subgroups. This has disadvantaged smaller patient subsets, such as children, who often cannot find drug products in dosage levels suitable for their requirements. In recent years, development of pharmaceutical mini-tablets has emerged as an attractive solution to this problem. These are small-size dosages that offer attractive features such as flexible and personalized drug dosing, ease of swallowing, and tailored drug release, making them an excellent choice for administering medicines to children. This study presents a novel technique for manufacturing pharmaceutical mini-tablets, using a drop-on-demand (DoD) printing system. In this method, a DoD system is used to generate precise droplets of a melt-based formulation, which are then captured and solidified in an inert solvent bath to produce individual mini-tablets. The study also evaluates the performance of this technique for various formulations, and quantifies two critical quality attributes (CQAs) of the resulting mini-tablets: content uniformity and dissolution behavior. The findings demonstrate that the manufactured mini-tablets can meet regulatory specifications for both CQAs, and that their release profiles can be customized by modifying the excipients used. The study also discusses promising areas of application and limitations of this technique.

Pharmaceutical Industry Perspective on the Non-Clinical Evaluation of Novel Excipients: Results From an Industry Survey Conducted by the IQ Novel Excipient Working Group.

Excipients are essential components within drug products that contribute significantly to their overall quality, effectiveness, and safety. There is a lack of global, harmonized guidance relating to the non-clinical testing of novel excipients which is perceived to create uncertainty and strategic risk, potentially hindering innovation and disincentivizing their use. To test these perceptions, the IQ Novel Excipient Working Group surveyed member companies regarding their main concerns and prior experience regarding the non-clinical evaluation of excipients. Of the 19 respondents, 13 provided, collectively, 33 non-clinical program examples supporting the development of novel excipients. Programs were distributed across a range of therapeutic areas and included a variety of drug modalities and administration routes. Package designs were variable, but where possible, employed the use of existing data, supplemented with new toxicology studies as appropriate. Of the programs which had submitted data to regional health authorities, only three received feedback requesting additional studies or that demonstrated differences in regional opinion. In addition, companies provided recommendations on how the current (or new) guidance related to non-clinical excipient evaluation (and other areas, such as Chemistry, Manufacturing, and Controls and databases) may be improved.

Cylindrical granules in the development of mesalazine solid formulations (â ): Physical properties, compression behaviors, and tableting performances.

Cylindrical granules have been employed in the pharmaceutical industry. However, to our knowledge, the study on the compressibility and tabletability of cylindrical granules has not been reported. This study aimed to explore the effects of the physical properties of cylindrical granules on the compression behaviors and the tableting performances, with mesalazine (MSZ) as a model drug. First, the six formulations of MSZ cylindrical granules were extruded by changing the ethanol proportion in the binder. Then, the physical characteristics of MSZ cylindrical granules were systematically studied. Subsequently, the compressibility and tabletability were evaluated using different mathematic models. It was worth noting that highly porous cylindrical granules possessed favorable compressibility and good tabletability due to the increased pore volume, reduced density, and decreased fracture forces. Finally, dissolution tests were conducted and highly porous granules showed higher dissolution rates than the less porous ones, but an opposite trend was observed for the corresponding tablets. This study proved the importance of physical properties in the tableting process of cylindrical granules and provided strategies to improve their compressibility and tabletability.

Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

Drug-Excipient Compatibility Study Through a Novel Vial-in-Vial Experimental Setup: A Benchmark Study.

Drug-excipient compatibility study (DECS) is one of the critical steps during pre-formulation studies to select the appropriate excipient to obtain a stable formulation/dosage form. As such, there is no recommended guideline for DECS. Further, the previously reported studies and protocols followed by various pharmaceutical industries are very lengthy and laborious. Therefore, to improve the existing study strategies and rapid screening of suitable excipients during formulation development, a novel vial-in-vial approach has been proposed. The devised approach was compared with the previously reported conventional approaches using six different drugs with multiple marketed formulations from different manufacturers for each drug. To validate the proposed novel approach, several reported strategies/methodologies have been executed such as exposure of formulations with and without primary packaging, crushed blend with and without water, and/or acetonitrile at accelerated stability condition of 40°C/75% RH for 3 to 6 months and compared with the novel approach. Eventually, all the samples were subjected to HPLC analysis to evaluate the degradation behaviour. The results suggested that the novel approach demonstrated discriminating results with significant degradation as compared to the conventional approaches. Consequently, exercising this methodology for screening the excipients is expected to shorten the drug development cycle by many folds. Moreover, it has also been anticipated that the developed novel approach would prevent the occurrence of late-stage surprises during stability studies.

Comparative assessment of solubility enhancement of itroconazole by solid dispersion and co-crystallization technique: Investigation of simultaneous effect of media composition on drug dissolution.

Solubility of the drug is an important property of the drug as it affects the release, absorption, dissolution rate and ultimately bioavailability of the drug. Hence, the poorly aqueous soluble drug, need to be processed, to enhance its solubility and dissolution. The Biopharmaceutical System of Classification (BCS) II drugs are poorly soluble and have high permeability. Though their good ability to permeate through the membrane make them clinically useful but the problem associated with the solubility restrict their clinical use. Therefore, there is need to improve the solubility of such drug molecules to get effective pharmacological action. Itraconazole (ITZ) is an antifungal agent used in the treatment of fungal infections having poor aqueous solubility as belonging to BCS class II. The present study was aim to enhance the solubility of ITZ by solid dispersion and co-crystallization techniques. Investigation of simultaneous effect of media composition on drug dissolution was also the objective of this work. The ITZ-SD and ITZ-CCs were prepared from ITZ and other excipients like PEG 4000, oxalic acid, fumaric and malic acid by solvent evaporation, kneading technique, slurry conversion and solvent drop grinding methods. The prepared ITZ-SD, ITZ-OA-CCs, ITZ-FA-CCs and ITZ-MA-CCs were evaluated for FTIR, DSC, PXRD, % yield, micromeritic properties. The optimized ITZ-SD and ITZ-CCs were used to compress a tablet and subject to post-compression parameters. The results of FTIR and DSC showed the absence of interaction between the drug and excipients. The PXRD pattern demonstrated the formation of crystalline structures with 6 folds increased in solubility during saturation solubility analysis. In vitro dissolution was carried out in dissolution media with different pH which shows the maximum release from ITZ-SD and ITZ-CCs in pH 6.8. This also revealed the highly pH dependent solubility and dissolution behavior of the weakly basic BCS class II drug (ITZ) with pKa value of 3.7. The overall results in this study indicated the potential of solid dispersion and co-crystals for enhancement of solubility of the poorly water-soluble drugs.

In vitro and in vivo assessment of structural integrity for HPCD complex@Liposome nanocomposites from ocular surface to the posterior segment of the eye.

Investigating the structural integrity of carriers in transit from ocular surface to ocular posterior segment is essential for an efficient topical drug delivery system. In this study, dual-carrier hydroxypropyl-ß-cyclodextrin complex@Liposome (HPCD@Lip) nanocomposites were developed for the efficient delivery of dexamethasone. Förster Resonance Energy Transfer with near-infrared I fluorescent dyes and in vivo imaging system were used to investigate the structural integrity of HPCD@Lip nanocomposites after crossing Human conjunctival epithelial cells (HConEpiC) monolayer and in ocular tissues. The structural integrity of inner HPCD complexes was monitored for the first time. The results suggested that 23.1 ± 6.4 % of nanocomposites and 41.2 ± 4.3 % of HPCD complexes could cross HConEpiC monolayer with an intact structure at 1 h. 15.3 ± 8.4 % of intact nanocomposites could reach at least sclera and 22.9 ± 1.2 % of intact HPCD complexes could reach choroid-retina after 60 min in vivo, which showed that the dual-carrier drug delivery system could successfully deliver intact cyclodextrin complexes to ocular posterior segment. In conclusion, in vivo assessment of structural integrity of nanocarriers is greatly significant for guiding the rational design, higher drug delivery efficiency and clinical transformation for topical drug delivery system to the posterior segment of the eye.

Elucidation of granulation mechanisms along the length of the barrel in continuous twin-screw melt granulation.

In the pharmaceutical industry, innovative continuous manufacturing technologies such as twin-screw melt granulation (TSMG) are gaining more and more interest to process challenging formulations. To enable the implementation of TSMG, more elucidation of the process is required and this study provides a better understanding of the granule formation along the length of the barrel. By sampling at four different zones, the influence of screw configuration, process parameters and formulation is investigated for the granule properties next to the residence time distribution. It showed that conveying elements initiate the granulation by providing a limited heat transfer into the powder bed. In the kneading zones, the consolidation stage takes place, shear elongation combined with breakage and layering is occurring for the reversed configurations and densification with breakage and layering for the forward and neutral configurations. Due to the material build-up in the reversed configurations, these granules are larger, stronger, more elongated and less porous due to the higher degree of shear and densification. This configuration also shows a significantly longer residence time compared to the forward configuration. Hence, the higher level of shear and the longer period of time enables more melting of the binder resulting in successful granulation.

Nitroso Impurities in Drug Products: An Overview of Risk Assessment, Regulatory Milieu, and Control Strategy.

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits.

Application of D-Optimal Mixture Design in the Development of Nanocarrier-Based Darifenacin Hydrobromide Gel.

BACKGROUND: Darifenacin hydrobromide, a BCS Class II drug, is poorly bioavailable due to extensive first-pass metabolism. The present study is an attempt to investigate an alternative route of drug delivery by developing a nanometric microemulsion-based transdermal gel for the management of an overactive bladder. METHODS: Oil, surfactant, and cosurfactant were selected based on the solubility of the drug, and surfactant: cosurfactant in surfactant mixture (Smix) was selected at a 1:1 ratio as inferred from the pseudo ternary phase diagram. The D-optimal mixture design was used to optimize the o/w microemulsion wherein the globule size and zeta potential were selected as dependable variables. The prepared microemulsions were also characterized for various physico-chemical properties like transmittance, conductivity, and TEM. The optimized microemulsion was gelled using Carbopol 934 P and assessed for drug release in vitro and ex vivo, viscosity, spreadability, pH, etc. RESULTS: Drug excipient compatibility studies showed that the drug was compatible with formulation components. The optimized microemulsion showed a globule size of less than 50 nm and a high zeta potential of -20.56 mV. The ME gel could sustain the drug release for 8 hours as reflected in in vitro and ex vivo skin permeation and retention studies. The accelerated stability study showed no significant change in applied storage conditions. CONCLUSION: An effective, stable, non-invasive microemulsion gel containing darifenacin hydrobromide was developed. The achieved merits could translate into increased bioavailability and dose reduction. Further confirmatory in vivo studies on this novel formulation, which is a cost-effective & industrially scalable option, can improve the pharmacoeconomics of overactive bladder management.

Application of design space and quality by design methodologies combined with ultra high-performance liquid chromatography for the optimization of the sample preparation of complex pharmaceutical dosage forms.

Accurate and precise analytical measurements play a significant role in assessments and decisions that are made throughout the drug development process. Developing a robust and reliable sample preparation is essential for drug product formulations to generate consistent results guaranteeing the product quality. However, due to the complex nature of the different pharmaceutical formulations with diverse excipients, developing robust sample preparation methods can be challenging and time consuming. Ensuring sample extraction robustness of pharmaceutical dosage forms becomes increasingly important with the potential impact to patient safety, product efficacy, and business efficiency. In this work we demonstrate and evaluate potential application of Quality by Design (QbD) principles to develop and optimize a robust sample preparation method in combination with the chromatographic analytical technique for a solid pharmaceutical dosage form. Practicability and utility of a QbD approach in optimization of sample preparation of this drug product are demonstrated as the active pharmaceutical ingredient (API) used in the drug product is proven to be highly sensitive for hydrolysis during analysis. Finally, the ultra-high-performance liquid chromatography method with UV detection that was applied during the design of experiments (DoE) was validated as per regulatory requirements. This systematic approach in analytics could provide guidance for the pharmaceutical industry in the development of robust sample preparation methods for different pharmaceutical dosage forms thus significantly reduce risks associated with the method transfers at clinical and commercial manufacturing sites.

Determining critical overlap concentration of polyethylene oxide to support excipient safety assessment of opioid products.

Intravenous administration of abuse-deterrent opioid products poses high safety risks, in part due to the presence of high molecular weight polymeric excipients. Previous in vivo studies in animal models have shown that the higher molecular weight (Mw) polymeric excipients like polyethylene oxide (PEO) were directly linked to such adverse responses as intravenous hemolysis and kidney damage. PEO polymers have been widely used in abuse-deterrent formulations (ADF) of opioid products, adding to concerns over the general safety of the opioid category due to the unknown safety risk from abuse via unintended routes. The current study focused on the determination of the critical overlap concentration (c*) at various PEO molecular weights to aid in explaining differences in observed adverse responses from previous animal studies on the intravenous administration of PEO solutions. Adverse in vivo responses may be related to the viscoelastic regime of the polymer solution, which depends not only on Mw but also on concentration. Having a localized polymer concentration in the blood above the c*, i.e., the transition from the dilute to semi-dilute entangled viscoelastic regime, may influence the flow behavior and interactions of cells in the blood. The relationship of c* to this combination of physical, chemical, and rheological effects is a possible driving force behind adverse in vivo responses.