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Vial breakage during or following freeze drying (lyophilization) is a well-known and documented phenomenon in the pharmaceutical industry. However, the underlying mechanism and probable root causes are not well characterized. Mostly, the phenomenon is attributed to the presence of crystallizing excipients, such as mannitol in the formulation, while other potential factors are often underestimated or not well studied. In this work we document a systematic multipronged approach to characterize and identify potential root cause(s) of vial breakage during lyophilization. Factors associated with formulation, product configuration, primary container and production process stress conditions were identified and their impact on vial breakage was studied in both lab and manufacturing scale conditions. Studies included: 1) strain gauge and lyophilization analysis for stress on glass vials with different formulation conditions and fill volumes, 2) manufacturing fill-finish process risk assessment (ex. loading and frictive force impact on the vials), and 3) glass vial design and ruggedness (ex. glass compression resistance or burst strength testing). Importantly, no single factor could be independently related to the extent of vial breakage observed during production. However, a combination of formulation, fill volume, and vial weakening processes encountered during at-scale production, such as vial handling, shelf loading and unloading, were identified to be the most probable root causes for the low levels of vial breakage observed. The work sheds light on an often-encountered problem in the pharmaceutical industry and the results presented in this paper argue against the simplistic root-cause explanations reported in literature. The work also provides insight into the possibility of implementing mitigative approaches to minimize or eliminate vial breakage associated with lyophilized drug products. [ABSTRACT FROM AUTHOR]

Assessing the robustness of a drug product formulation and manufacturing process to variations in raw material (RM) properties is an essential aspect of pharmaceutical product development. Motivated by the need to demonstrate understanding of attribute-performance relationships at the time of new product registration and for subsequent process maintenance, we review practices to explore RM variations. We describe limitations that can arise when active ingredients and excipients invariably undergo changes during a drug product lifecycle. Historical approaches, such as Quality-by-Design (QbD) experiments, are useful for initial evaluations but can be inefficient and cumbersome to maintain once commercial manufacturing commences. The relatively miniscule data sets accessible in product development – used to predict response to a hypothetical risk of variation – become less relevant as real-world experience of actual variability in the commercial landscape grows. Based on our observations of development and manufacturing, we instead propose a holistic framework exploiting a hierarchy of RM variability, and challenge this with common failure modes. By explicitly incorporating higher ranking RM variations as perturbations, material-conserving experiments are shown to provide powerful and enduring robustness data. Case studies illustrate how correctly contextualizing such data in formulation and process development can avoid the traps of historical QbD approaches and become valuable for evaluating changes occurring later in the drug product lifecycle. [ABSTRACT FROM AUTHOR]

Aflibercept is a recombinant fusion protein that is commercially available for several ocular diseases impacting millions of people worldwide. Here, we use a case study approach to examine alternative liquid formulations for aflibercept for ocular delivery, utilizing different stabilizers, buffering agents, and surfactants with the goal of improving the thermostability to allow for limited storage outside the cold chain. The formulations were developed by studying the effects of pH changes, substituting amino acids for sucrose and salt, and using polysorbate 80 or poloxamer 188 instead of polysorbate 20. A formulation containing acetate, proline, and poloxamer 188 had lower rates of aggregate formation at 4, 30, and 40°C when compared to the marketed commercial formulation containing phosphate, sucrose, sodium chloride, and polysorbate 20. Further studies examining subvisible particles after exposure to a transport stress and long-term stability at 4°C, post-translational modifications by multi-attribute method, purity by reduced and non-reduced capillary electrophoresis, and potency by cell proliferation also demonstrated a comparable or improved stability for the enhanced formulation of acetate, proline, and poloxamer 188. This enhanced stability could enable limited storage outside of the cold chain, allowing for easier distribution in low to middle income countries. [ABSTRACT FROM AUTHOR]

N- nitrosamines are likely human carcinogens. After N- nitrosamine contaminants were detected in pharmaceutical products in 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of N- nitrosamines in drug products. One strategy to inhibit the formation of N -nitrosamines during the manufacture and storage of drug products involves the incorporation of nitrite scavengers in the formulation. Diverse molecules have been tested in screening studies including the antioxidant vitamins ascorbic acid and α-tocopherol, amino acids, and other antioxidants used in foods or drugs, for inclusion into drug products to mitigate N- nitrosamine formation. This review article outlines key considerations for the inclusion of nitrite scavengers in oral drug product formulations. [ABSTRACT FROM AUTHOR]

Enzymatic hydrolysis of polysorbate in drug products is a major challenge for the biopharmaceutical industry. Polysorbate hydrolysis caused by host cell proteins (HCPs) co-purified during bioprocessing can reduce the protective effects of the surfactant for the active pharmaceutical ingredient and cause the accumulation of low-solubility degradation products over the long-term storage. The identities of such HCPs are elusive due to their extremely low concentrations after the efficient purification processes of most biopharmaceuticals. In this work, 20 enzymes—selected for their known or putative hydrolytic activity and potential to degrade polysorbate—were recombinantly expressed, purified, and characterized via orthogonal methods. First, these recombinant HCPs were assessed for hydrolytic activity against a fluorogenic esterase substrate in a recently-developed, high-throughput assay. Second, these HCPs were screened for hydrolytic activity against polysorbate in a representative mAb formulation. Third, HCPs that displayed hydrolytic activities in the first two assays were subjected to more detailed characterization of their enzyme kinetics against polysorbates. Finally, these HCPs were evaluated for substrate specificity towards different sub-species of polysorbates. This work provides critical new insights for targeted LC-MS/MS approaches for identification of relevant polysorbate-degrading enzymes and supports improvements to remove such HCPs, including knockouts or targeted removal during purification. [ABSTRACT FROM AUTHOR]

The performance of pharmaceutical dosage forms relies heavily on the characteristics of the excipients that are incorporated into the drug product during the manufacturing process. Therefore, it is imperative that formulators are able to accurately and completely specify the key chemical and physical properties of those excipients. Current approaches to describing excipients are outdated and inadequate for the needs of the 21st century and in this article we highlight the benefits of a more systematic and comprehensive approach to specifying and controlling excipient properties. We hope that this will prompt the users, suppliers, and manufacturers of excipients to take a careful look at current approaches and develop tangible proposals for attaining an enhanced future state. [ABSTRACT FROM AUTHOR]

Multi-injection pharmaceutical products such as insulin must be formulated to prevent aggregation and microbial contamination. Small-molecule preservatives and nonionic surfactants such as poloxamer 188 (P188) are thus often employed in protein drug formulations. However, mixtures of preservatives and surfactants can induce aggregation and even phase separation over time, despite the fact that all components are well dissolvable when used alone in aqueous solution. A systematic study is conducted here to understand the phase behavior and morphological causes of aggregation of P188 in the presence of the preservatives phenol and benzyl alcohol, primarily using small-angle x-ray scattering (SAXS). Based on SAXS results, P188 remains as unimers in solution when below a certain phenol concentration. Upon increasing the phenol concentration, a regime of micelle formation is observed due to the interaction between P188 and phenol. Further increasing the phenol concentration causes mixtures to become turbid and phase-separate over time. The effect of benzyl alcohol on the phase behavior is also investigated. [ABSTRACT FROM AUTHOR]

Many monoclonal antibody (mAb) solutions exhibit high viscosity at elevated concentrations, which prevents manufacturing and injecting of concentrated mAb drug products at the small volumes needed for subcutaneous (SC) administration. Addition of excipients that interrupt intermolecular interactions is a common approach to reduce viscosity of high concentration mAb formulations. However, in some cases widely used excipients can fail to lower viscosity. Here, using infliximab and ipilimumab as model proteins, we show that caffeine effectively lowers the viscosity of both mAb formulations, whereas other common viscosity-reducing excipients, sodium chloride and arginine, do not. Furthermore, stability studies under accelerated conditions show that caffeine has no impact on stability of lyophilized infliximab or liquid ipilimumab formulations. In addition, presence of caffeine in the formulations does not affect in vitro bioactivities of infliximab or ipilimumab. Results from this study suggest that caffeine could be a useful viscosity reducing agent that complements other traditional excipients and provides viscosity reduction to a wider range of mAb drug products. [ABSTRACT FROM AUTHOR]

Sugar alcohols reduce oral drug bioavailability by osmotic effects, but the magnitude of these effects differs among different drugs. This study aimed to identify the drug-related critical attributes of osmotic effects and estimate the impact of a "practical" sugar alcohol dose on the pharmacokinetics of various molecules using modeling and simulation approaches. We developed a physiologically based biopharmaceutics model that considers the dose-dependent effects of sugar alcohols on the gastrointestinal physiology. The developed model captured the effects of sugar alcohols on ranitidine hydrochloride, metoprolol tartrate, theophylline, cimetidine, and lamivudine. Sensitivity analysis provided quantitative insights into the effects of sugar alcohols dependent on different drug permeability. In addition, our developed model indicated for the first time that a high systemic elimination rate is crucial for the reduction in maximum plasma concentration even for highly permeable drugs. Nonetheless, mannitol/sorbitol level of less than 400 mg had minor effects on the pharmacokinetics of the most sensitive drugs, indicating a provisional no-effect threshold dose. This mechanistic approach provides comprehensive estimation of osmotic effects on variety of drugs. Subsequently, these findings may invoke scientific discussion on the criteria for excipient changes in the context of biowaiver guidelines (e.g. biopharmaceutics classification system-based biowaiver). [ABSTRACT FROM AUTHOR]

Different types and quality grades of polysorbate (PS) were subjected to oxidative stress (in absence of protein), and novel oxidation markers were discovered by our newly developed liquid chromatography-mass spectrometry (LC-MS) screening method. These markers confirmed that the more homogeneous, PS grades, such as PS80 all-oleate grade (compliant with Chinese pharmacopoeia) and PS20 all-laurate grades are more prone to oxidative degradation compared to their multicompendial grade analogues. In a case study with pharmaceutically relevant monoclonal antibody formulations, we could confirm that the novel oxidation markers are also found in presence of protein. To the best of our knowledge, this is the first report on monitoring of PS oxidation markers in protein containing samples with the help of LC-MS. Based on the observations made in the PS degradation studies, a new hypothesis regarding the mechanism of oxidative PS degradation is suggested: PS oxidation primarily takes place in the PS micelles. This hypothesis was supported experimentally, PS oxidation could no longer be detected if PS micelles were dissolved by tert-butanol. Physiochemical parameters of PS micelles such as density of micelle cores, heterogeneity of PS fatty acid composition, micelle composition and trace metal ions are key driving factors of PS oxidation. [ABSTRACT FROM AUTHOR]

This review provides insight into the use of boric acid as a pharmaceutical, a buffer, and an adjuvant/excipient in pharmaceutical formulations. Boric acid is a Lewis acid with a pKa of 8.92–9.24 that is sensitive to temperature, ionic strength, and concentration. The pKa varies with concentration because of polymerization above 0.02 M. Boric acid reacts reversibly with alcohols, especially 1,2-diols including carbohydrates, with carboxylic acids, thiols, and amines. These esters/adducts, are also Lewis acids with lower pKa values. Boric acid can stabilize some materials while catalyzing the degradation of others. Boric acid is used in various dermal and women's hygiene products because of its mild antibacterial and antifungal activity. In ophthalmic products, it is used as a buffer and in combination with other preservatives to broaden the prservative spectrum. Boric acid has been used reluctantly in parenteral products but appears to be quite safe at low doses. However, at high exposure, toxicity, including death, has been reported in humans, especially in children. Animal toxicities have also been noted, including reductions in male sperm counts. Boric acid is well absorbed on oral dosing. Its biological half-life is about 21 h in humans and has an affinity for some tissues, especially bone. [ABSTRACT FROM AUTHOR]

NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients. Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-assisted phenomenon and surface characteristics of mannitol were hypothesized to play important role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on 2 surfaces of mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in the presence of rougher surface (t ind < 1 min) compared with smooth surface (t ind = 49.28 min). This was attributed to higher porosity (75%) and surface polarity (~1.25-fold) of rough surface as compared with smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate. These findings can be utilized for generating crystalline solid dispersions using spray drying in the presence of mannitol. The crystalline solid dispersions can be used for the development of oral solid dosage forms. [ABSTRACT FROM AUTHOR]

This commentary illustrates and summarizes some of the many issues with dosage forms and drug delivery that arise in everyday practice for clinicians caring for pediatric patients. While advances in drug development for children and expansion of labeling information in this age group have made great strides in improving care, there is much to be desired in the area of dosage forms. From liquids that are unpalatable to the need for extemporaneous compounding of parenteral doses in syringes that are meant for immediate use but used to store medications for hours to weeks, the list of challenges is long. Many of these problems exist for drugs which have long been generic, but some problems have arisen from new drugs as well. Pediatric clinicians and dosage form developers should work together to create solutions. [ABSTRACT FROM AUTHOR]

Specifically tailored amino acid–based formulations were previously shown to have a high potential to avoid stress-mediated degradation of complex molecules such as monoclonal antibodies and viral vectors. By using adenovirus 5 (Ad5) as a model, we studied whether such formulations may also efficiently protect viral vectors in thermal stress experiments and during long-term liquid storage. Algorithm-based amino acid preselection using an excipient database and subsequent application of design of experiments (DoE) in combination with a 37°C challenging model enabled the prediction of long-term storage stability of Ad5. By statistical analysis of the Ad5 infectivity, amino acids with significant influence on Ad5 stability were detected after 2 and 3 weeks of liquid storage at 37°C. Ad5 formulations comprising positively selected amino acids did not reveal any loss of infectivity after 24 months in liquid storage at 5°C. By contrast, a 2 log reduction after 3 months and complete loss of infectivity after 18 months was observed with a standard viral vector formulation. By an optimization round, we designed a simple and well-balanced formulation avoiding MgCl 2 , previously considered essential in Ad5 formulations. This work demonstrates the efficacy of an algorithm-based development approach in the formulation development for viral vectors. [ABSTRACT FROM AUTHOR]

Excipients used in lyophilized protein drug products are often selected by a trial-and-error method, in part, because the analytical methods used to detect protein-excipient interactions in lyophilized solids are limited. In this study, photolytic labeling was used to probe interactions between salmon calcitonin (sCT) and excipients in lyophilized solids. Two diazirine-derived photo-excipients, photo-leucine (pLeu) and photo-glucosamine (pGlcN), were incorporated into lyophilized solids containing sCT, together with an unlabeled excipient (sucrose or histidine) at prelyophilization pH values from 6 to 9.9. Commercially available pLeu was selected as an ionizable photo-excipient and amino acid analog, while pGlcN was synthesized as an analog of sugar-based excipients. Photolytic labeling was induced by exposing the solids to UV light (365 nm, 30-60 min), and the resulting products were identified and quantified with liquid-chromatography mass spectrometry. The distribution of photo-reaction products was affected by the photoreactive reagent used, the type of unlabeled excipient, and the solution pH before lyophilization. When other components of the solid were identical, the extent and sites of labeling on sCT were different for pGlcN and pLeu. The results suggest that ionizable and nonionizable excipients interact differently with sCT in lyophilized solids and that photo-excipients can be used to map these interactions. [ABSTRACT FROM AUTHOR]

The purpose of this study is to assess some of the variables determining the aldol-like condensation of pyruvic acid (1), a peroxide scavenger, in aqueous solution to parapyruvic acid and higher oligomers. Its stability is compared to 3 other α-keto carboxylic acids, 2 with sterically hindered methylene groups alpha to the keto functionality (2-3) and phenylglyoxylic acid (4) with no methylene group. High-performance liquid chromatography, nuclear magnetic resonance, and liquid chromatography mass spectroscopy techniques are used in the kinetics and product analyses. 1 condensation is concentration dependent and base catalyzed above pH 7, consistent with the reaction mechanism proceeding through the attack of the fraction of the methylene group, alpha to the keto group, in its anionic form, at the keto group of a second molecule of 1. The major product is confirmed to be parapyruvic acid, but higher-order oligomers are also observed. All 3 of the other α-keto carboxylic acids 2-4 are considerably less reactive, with 4 being completely stable. Stable solutions of 1 can be prepared by the use of relatively dilute solutions maintained at slightly acidic pH values. 1 prevents the oxidation of methionine on addition of hydrogen peroxide. [ABSTRACT FROM AUTHOR]

The aim was to compare the sensitivity of different grades of polysorbate 20 (PS20) and polysorbate 80 (PS80) against enzymatic hydrolysis and oxidative degradation in pharmaceutically relevant buffer systems. For this purpose, a fast liquid chromatography charged aerosol detection method was developed which allows to (1) differentiate between hydrolytic and oxidative PS degradation and (2) to monitor the PS decay over time. Systematic enzymatic and oxidative forced degradation studies were conducted with multicompendial PS20 and PS80, as well as all-laurate PS20 and all-oleate PS80 (with >98% oleic acid, as required by the Chinese Pharmacopoiea since 2015). No differences in the sensitivity toward enzymatic degradation were observed between multicompendial PS and high purity grade PS. However, all-laurate PS20 and all-oleate PS80 have a higher predisposition for oxidative degradation as compared to multicompendial PS20 and PS80. The buffer system used within the study played thereby a key role: histidine showed a protective effect against hydrogen peroxide–induced oxidation, whereas hydrogen peroxide oxidation of PS in acetate buffer was severe under the experimental conditions. Furthermore, ethylenediaminetetraacetic acid protected PS20 and PS80 against oxidative degradation in histidine buffer. [ABSTRACT FROM AUTHOR]

Abstract Oral pediatric formulations are either ready-to-use or require manipulation and multiuse or single-use. Strong encouragement for preservative-free pediatric formulations has resulted in fewer multiuse solutions or suspensions in favor of single-use solid oral dosage forms. This updated review covering new pediatric formulations marketed in the United States of America, Europe, and Japan spanning the years 2007 to mid-2018 identified 16 types of pediatric oral formulations of which 7 are ready-to-use and 9 require manipulation, and 51 total new pediatric oral formulations of which 21 are ready-to-use and 30 require manipulation. Ready-to-use formulations include oral solution, oral suspension, oral soluble film, tablet, scored tablets, orally disintegrating tablet, chewable tablet, and mini-tablets. Formulations requiring manipulation include sprinkle capsule, powder for oral solution, powder for oral suspension, granules for oral suspension, oral powder, oral granules, tablet, dispersible tablet, dispersible scored tablet, tablet for oral suspension, and mini-tablets (oral granules). Significant advances in packaging technology include filling mini-tablets, granules, or powders into sachets, stick packets, blisters, and 2-piece capsules. The future of pediatric oral formulations will increasingly be with user-friendly, preservative-free, taste-masked formulations including multiparticulate single-use solid dosage forms including mini-tablets, orally disintegrating tablets, and sprinkle capsules with or without a specialized package configuration. [ABSTRACT FROM AUTHOR]

A well-controlled clinical trial is one of the critical steps to evaluate the efficacy and safety of novel medicaments. The use of a placebo is employed in several types of clinical trials in order to set a baseline against which the efficacy of the investigational drug is evaluated. An ideal placebo should match the final formulation as close as possible such that the patient/health care providers are unable to identify any difference. This is difficult for high concentration biologic intended for subcutaneous administration, mainly because of their color and viscosity. Currently, the challenge is overcome by using opaque labels or by unblinded pharmacists, both solutions are expensive. The present study provides an efficient alternative where a protein excipient (recombinant albumin) is used to prepare a placebo for biologicals. We have demonstrated that the use of recombinant albumin can match the color of the active when used in the right quantity. The evaluated solution is highly flexible and has the potential to match the color of different biopharmaceuticals at different concentrations/formulations. [ABSTRACT FROM AUTHOR]

Abstract Molecular dynamics simulations can be applied to explore the complex liquid phase behavior of lipid-based formulations and the gastrointestinal tract lumen. In order for the results from these simulations to be of value, the manner in which molecules interact with both aqueous and oil phases present needs to be as correct as possible. An existing molecular dynamics force field, GROMOS 53a6, was demonstrated to poorly reproduce the partitioning of straight-chain alcohol and short-chain polyethylene glycol (PEG) molecules between octanol and water phase (logP), with the molecules too hydrophobic. Force field parameters for Lennard-Jones interactions between CH2 and CH3 with water oxygen were adjusted to reproduce the experimental octanol logP, with all other Lennard-Jones and force field parameters left untouched. This parameter set, called 53a6 DBW , was subsequently used to recalculate straight-chain alcohol and short-chain PEG molecules, with significant improvement in the values obtained. Simulations of a nonionic surfactant in water, octaethylene glycol monocaprylate, were also performed to observe the aggregation behavior. 53a6 DBW demonstrated significant improvements in water interactions with the PEG chains, well hydrating the PEG groups, and allowing the formation of micelles. Further improvements and evaluation of the improved parameter set are ongoing. [ABSTRACT FROM AUTHOR]

Abstract Hydrogen bonds (HBs) in amorphous solid dispersions may influence physical stability through effects on both drug miscibility and mobility. Amorphous solid dispersions containing the HB-donor ibuprofen (IBP) alone or with one of four model polymers (poly(vinyl pyrrolidone) [PVP], poly(vinyl pyrrolidone/vinyl acetate) [PVP/VA], poly(vinyl acetate) [PVA], or polystyrene [PST]) were monitored by molecular dynamics simulation. HB distributions and contributions of electrostatic, van der Waals, and internal interactions to miscibility and mobility were analyzed versus drug concentration. The probability of IBP-IBP HBs decreases markedly (0.6→0.0) with dilution (100→10% drug) in PVP due to IBP-PVP HBs while dilution in the nonpolar PST has a more modest effect on IBP-IBP HB probability (0.6→0.3). Concentration-dependent Flory-Huggins interaction parameters (χ) were determined to assess drug-polymer miscibility. χ IBP-PVP values were −0.9 to −1.8 with a plateau near 50% w/w PVP, whereas χ IBP-PST fluctuated near zero (−0.1 to 0.3), suggesting that IBP is more soluble in PVP than in PST. χ IBP-polymer values in polymers varying in pyrrolidone/acetate composition were in the order PVP (most favorable) > PVP/VA > PVA (least favorable). Decreased local mobility of IBP measured by the atomic fluctuation correlates with more IBP-PVP HBs with increasing PVP content. The opposite trend in IBP-PST may arise from IBP-IBP HB disruption on dilution. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer resistance protein (BCRP) transporter is an efflux transporter that utilizes energy from adenosine triphosphate hydrolysis to push its substrates, regardless of the concentration gradient. Its presence on the apical membrane of the intestinal mucosa is a major obstacle for the intestinal absorption of its substrates. In this study, we examined the effects of various pharmaceutical excipients on the intestinal transport and absorption of sulfasalazine, a BCRP substrate. Four excipients, including 0.05% and 0.075% BL-9EX, 0.01% and 0.05% Brij 97, 0.075% Labrasol, and 0.05% and 0.1% Tween 20 decreased the secretory transport of sulfasalazine in an in vitro diffusion chamber. Further investigation in an in situ closed loop experiment in rats showed that 0.05% and 0.1% BL-9EX and 0.1% Brij 97 effectively enhanced the intestinal absorption of sulfasalazine while maintaining minimal toxicity to the intestinal mucosa. However, 0.1% Brij 97 also increased the intestinal absorption of 5(6)-carboxyfluorescein, a paracellular marker compound. These findings suggest that BL-9EX might effectively inhibit the BCRP-mediated efflux of sulfasalazine in vivo , indicating that BL-9EX could improve the intestinal absorption of sulfasalazine and other BCRP substrates. [ABSTRACT FROM AUTHOR]

Abstract Tablets disintegration is often the result of a size expansion of the tablets. In this study, we quantified the extent and direction of size expansion of tablets during disintegration, using readily available techniques, that is, a digital camera and public domain image analysis software. After validating the method, the influence of disintegrants concentration and diluents type on kinetics and mechanisms of disintegration were studied. Tablets containing diluent, disintegrant (sodium starch glycolate, crospovidone, or croscarmellose sodium), and lubricant were prepared by direct compression. Projected area and aspect ratio of the tablets were monitored using image analysis techniques. The developed method could describe the kinetics and mechanisms of disintegration qualitatively and quantitatively. Sodium starch glycolate and crospovidone acted purely by swelling and shape recovery mechanisms. Instead, croscarmellose sodium worked by a combination of both mechanisms, the extent of which changed depending on its concentration and the diluent type. We anticipate that the method described here could provide a framework for the routine screening of tablets disintegration using readily available equipment. [ABSTRACT FROM AUTHOR]

Abstract While there are many standard-setting health care organizations, the United States Pharmacopeial Convention's (USP) role includes the creation of documentary and physical standards for therapeutics, including chemical drugs, excipients, and biologics. Despite the ubiquity of these standards, little work has been carried out to characterize and quantify their value. We reviewed the peer-reviewed and gray literature relevant to such evaluations. The review yielded 36 articles, focused variously on accreditation and other standards in health care, the broad impact of pharmacopeial standards and evaluations of specific USP standards. We did not find any study quantifying the impact of USP or other pharmacopeial standards, but many reports have been published that suggest the utility of USP standards to drug development, quality assurance, and public health. Frequently cited areas of impact include equitably advancing the analytical capabilities of manufacturers; enabling the creation of legally enforceable naming conventions; detecting mislabeled and substandard drugs in the marketplace, especially in the context of increased globalization of drug markets; and facilitating the harmonization of diverse international drug quality standards. Our insights provide opportunities for empiric assessments of the effects of USP standards on important outcomes including their promotion of efficient drug development, market competition, drug quality, and patient safety. [ABSTRACT FROM AUTHOR]

Sticking and picking during tablet manufacture has received increasing interest recently, as it causes tablet defects, downtime in manufacturing, and yield losses. The capricious nature of the problem means that it can appear at any stage of the development cycle, even when it has been deemed as low risk by models, tests, and previous experience. In many cases, the problem manifests when transferring the process from one manufacturing site to another. Site transfers are more common now than in previous times because of the multinational nature of drug product manufacturing and the need for redundancy in manufacturing networks. Sticking is a multifactorial problem, so one single “fix” is unlikely to solve it completely, and “solutions” addressing one problem may exacerbate another. A broad-based strategy involving the API, formulation, tablet tooling, and the manufacturing process is the most likely approach to provide a robust and lasting solution. When faced with a sticking problem for the first or subsequent time, the formulator should address, in a structured way, a range of possible causes and remedies. In this article, we focus on current research and practice; on some of the common causes of sticking; mitigation and resolution strategies and solutions; and possible future directions in research. [ABSTRACT FROM AUTHOR]

Poorly absorbable sugar alcohols (e.g., mannitol, sorbitol, and maltitol) are the excipients frequently contained in pediatric dosage forms. Due to their osmotically active properties, certain amount of sugar alcohols reportedly reduces oral bioavailability of concomitant drugs. This fact implies the possible pharmacokinetic interaction between orally administered drug and sugar alcohols which are present in other concomitant medications. The purpose of this study was to identify the possibility and likeliness of the osmotically active excipient-induced pharmacokinetic interaction in pediatric polypharmacy. Previously developed in silico model that captured the osmotic effect of sugar alcohols in adults was expanded to pediatric population. This mathematical model successfully explained the impaired bioavailability of lamivudine by the co-administered sorbitol in other dosage forms. In the meantime, sugar alcohol contents in marketed pediatric dosage forms were investigated by reverse engineering technology. Considering the critical administration dose of sugar alcohols estimated by in silico model, it was revealed that 25 out of 153 pediatric dosage forms were identified as possible perpetrators even under the approved administration and dosage in Japan. This study shed light on the potential pharmacokinetic interaction that cannot be dismissed throughout the pediatric pharmaceutical dosage form design and development. [Display omitted] [ABSTRACT FROM AUTHOR]