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Background: The aim of this work was to develop and validate sensitive and efficient analytical methods for estimating systemic drug exposure and residual drug following the application of topical delivery systems. Materials & methods: Lidocaine was extracted using a liquid–liquid extraction technique from commercial topical products and analyzed using ultra high-performance liquid chromatography. A separate LC–MS/MS method was developed for analyzing human serum samples. Results & conclusion: The developed methods were successfully applied for estimating lidocaine content in two commercial products demonstrating 97.4–104.0% for product A and 105.0–110.7% for product B. The LC–MS/MS method displayed successful analysis of lidocaine from human serum samples. The developed methods are recommended for quantifying systemic exposure and residual drug analysis of topical systems.

A primary anti-coagulant narrow therapeutic index warfarin sodium poses a high risk of thrombosis or excessive bleeding with a sudden death. The root cause for these risks are not well established....

In the literature, it is reported that eutectics lead to the enhanced dissolution of a poorly soluble compound. However, the solubility theory suggests that since crystal structures of two components are unchanged that all else being equal, the dissolution rates of a fused mixture (FM) should be the same as a physical mixture (PM). The influence of crystal lattice energy on dissolution profiles was investigated using the PM and FM. Experimental phase diagrams constructed using differential scanning calorimetry data were compared with those theoretically derived. Deviation of the experimental phase diagram curves from the theoretical model indicates the nonideal behavior of both systems (ibuprofen/poly(ethylene glycol)-6000 and acetaminophen/caffeine). Both the binary systems showed an increase in the dissolution rate of the PM and FM. However, the dissolution from the PM was comparable with the FM's dissolution profile. The theoretical solubility calculations using the modified solubility equation showed that the use of the eutectic temperature instead of the drug's melting point should give a 3-4-fold increase in drug solubility. However, the correlation between dissolution and solubility calculation showed that the FM did not improve the dissolution when compared with the respective PM's dissolution profile. The proposed explanation is that the unchanged crystal lattice energy in eutectics still limits the solubility and therefore the dissolution rate.

The molecular basis of adhesion leading to sticking was investigated by exploring the correlation between thermal analysis and molecular simulations. It is hypothesized that intermolecular interactions between a drug molecule and a punch face are the first step in the adhesion process and the rank order of adhesion during tablet compression should correspond to the rank order of the energies of these interactions. In the present study, the sticking propensity was investigated using ibuprofen, flurbiprofen, and ketoprofen as model substances. At the intermolecular level, a thermal analysis model was proposed as an experimental technique to estimate the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen in a DSC aluminum pan. The linear relationship was established between the enthalpy of vaporization and sample mass to demonstrate the accuracy of the instruments used. The threshold mass for ibuprofen, flurbiprofen, and ketoprofen was determined to be 107, 112, and 222 μg, respectively, after three replicate measurements consistent with the experimental results. Ketoprofen showed a 2-fold higher threshold mass compared to ibuprofen and flurbiprofen, which predicts that ketoprofen should have the highest sticking propensity. Computationally, the rank order of the work of adhesion between ibuprofen, flurbiprofen, and ketoprofen with the metal surface was simulated to be -75.91, 44.75, and -96.91 kcal/mol, respectively, using Materials Studio. The rank order of the interaction between the drug molecule and the iron superlattice decreases in the order ketoprofenibuprofenflurbiprofen. The results indicate that the thermal model can be successfully implemented to assess the sticking propensity of a drug at the molecular level. Also, a new molecular simulation script was successfully applied to determine the interaction energy of the drug molecule upon contact with iron.

Phenytoin sodium, a salt of 5,5-diphenylimidazolidine-2,4-dione, or phenytoin, is commercially available in various dosage forms for its anti-epileptic properties to treat and prevent seizures. The title compound, poly[aquatris(μ3-4,4-diphenyl-2,5-dioxoimidazolidin-1-ido)trimethanoltrisodium(I)], [Na3(C15H11N2O2)3(CH4O)3(H2O)1.08] n , a methanol solvate and hydrate of phenytoin sodium, forms a modulated crystal structure that consists of a supercell made up of three close-to-identical repeat units. Each of the basic fragments consists of one phenytoin anion, a sodium cation, and either a methanol, or a methanol and a water molecule coordinated to the sodium ion, yielding a formula unit of Na(C15H11N2O2)(CH3OH) x (H2O) y for each of the three segments (x, y = 0 or 1; x + y = 1 or 2). Modulation along the b axis is introduced due to the presence or absence of water or methanol molecules at sodium and by the alternating torsion angles of one of the two phenytoin phenyl rings. Individual segments within the asymmetric unit are linked by covalent Na—O and Na—N bonds, with each sodium ion coordinated to one anionic amide N atom and three keto O atoms. The Na—N and one of the Na—O bonds connect (C15H11N2O2)·Na units along the modulation direction, creating an infinite [(C15H11N2O2)·Na]_{\infty} chain that is further stabilized by intramolecular N—H...O hydrogen bonding parallel to [010]. The second Na—O bond connects this chain with a symmetry-equivalent copy of itself created by a screw-axis operation, yielding double strands of [(C15H11N2O2)·Na]_{\infty} chains. Two of these double strands, propagating in opposite directions, constitute the content of the unit cell. Neighboring double strands are connected with each other to form layers perpendicular to the a axis, tethered together via O—H...O hydrogen bonds involving the water and methanol molecules. In addition to modulation, each of the repeat units also exhibits disorder of the modulated segments. Phenyl rings of each repeat unit are rotationally disordered, and sodium-coordinated methanol and water molecules are also positionally disordered and/or partially occupied. The solvated structure reported here, while not matching the patterns reported for any of the known forms of phenytoin sodium, does provide a first insight into the complications and complexities involved in resolving the structure of anhydrous phenytoin sodium.

The current research work focuses on understanding the reported discrepancies and our observations in the dissolution profiles of warfarin sodium tablets and potential patient-based failure modes during oral warfarin therapy. It was hypothesized that freely soluble crystalline warfarin sodium (WARC) at first transforms into noncrystalline warfarin sodium (WARNC) under stress conditions. The WARC → WARNC conversion facilitates the rapid formation of the poorly soluble unionized form, which could lead to dissolution failures and potential poor in vivo performance. Depressed warfarin concentrations locally in the gastrointestinal tract (GIT) may in turn lead to inadequate absorption and thereby affect bioavailability. A low volume two-stage dissolution method was developed to mimic in vivo GIT conditions. Warfarin sodium tablets exposed to room temperature and 75% relative humidity for 1 week showed approximately 23% decrease in drug release. The decline in drug release supports the hypothesis that WARNC is converted to the unionized form faster than WARC does under the same conditions. Solid state characterization (powder X-ray diffractometry and differential scanning calorimetry) data demonstrated the disproportionation of warfarin sodium to unionized warfarin after solubility and dissolution studies. The findings support the hypothesis and a possible failure mode of warfarin sodium tablets. This work is a second case study from our laboratory on narrow therapeutic index drug products in which the instability of the solid state of the drug substance is potentially responsible for observed clinical failures.

Dissolution testing and solubility determinations in different biorelevant media have gained considerable interest in the pharmaceutical industry from early-stage development of new products to forecasting bioequivalence. Among all biorelevant fluids, the preparation of fed-state simulated gastric fluid (FeSSGF) and handling of samples from dissolution/solubility testing in FeSSGF is considered to be relatively challenging. Challenges include maintaining the stability of FeSSGF medium upon sampling, filtration, and mitigating analytical interference of excipients and milk components. To overcome these challenges, standard and uniform working practices are required that are not only helpful in preparation of stable FeSSGF but also serve as a harmonizing guide for the collection of dissolution/solubility samples and their subsequent processing (i.e., handling and assay). The optimization of sample preparation methodology is crucial to reduce method-related variance by ensuring specificity, robustness, and reproducibility with acceptable recovery of the analytes. The sample preparation methodology includes a combination of techniques including filtration, solvent treatment, and centrifugation to remove the interfering media-related components and excipients from the analyte. The analytes of interest were chromatographically separated from the interfering analytes to quantify the drug concentration using the new high-performance liquid chromatography methods with ultraviolet detection. The methods developed allow rapid sample preparation, acceptable specificity, reproducible recoveries (greater than 95% of label claim), and quantification of study drugs (ibuprofen and ketoconazole). The sample preparation technique and method considerations provided here for ibuprofen and ketoconazole can serve as a starting point for solubility and dissolution testing of other small molecules in FeSSGF.

Anisotropic features with other crystallographic properties like d-spacing, and attachment energy (Eatt) can predict material performance during the secondary pharmaceutical processing. A newly developed state-of-the-art compression cell lodged in a powder X-ray diffractometer was used to measure anisotropic Young’s moduli (YM) of flufenamic acid (FFA) polymorphs in this study. Methodology is based on the generation of a single crystal deformation in this cell, which reflects as a change in the d-spacing in the PXRD pattern. Anisotropic YM was calculated from such information gathered along different FFA planes. Measured FFA crystallographic molecular features were concatenated to understand macroscopic compaction (Heckel and Shapirao’s parameters) and tableting performance. Block shaped crystals of FFA form I, and III after initial characterization with SEM, DSC, PXRD, and FTIR were compressed normal to X, Y, and Z-planes, identified from calculated PXRD pattern using the reported single crystal structure. YM of X and Y planes of form I was significantly higher than corresponding planes of form III. Z plane of form III showed significantly higher YM than that for form I. Low YM of form III can be attributed to its large d-spacing regardless of their high Eatt than form I, as well as orientation of supramolecular acid dimer (O H⋯O) homosynthon chains in the FFA planes. FFA form I stiffness was further confirmed with lower densification and higher yield pressure of deformation than form III. Clearly, form III exhibited better compressibility, compactibility, and tableting performance than form I due to favorable molecular and macroscopic features. Thus, developed anisotropic measurement approach can be used to distinguish material performance in the early development stage of the pharmaceutical processes.

A contribution of crystal structure, mechanical moduli, and macroscopic compression properties of flufenamic acid (FFA) and its cocrystal with nicotinamide (NIC) was evaluated to predict their compaction performance. The FFA:NIC cocrystal formation was confirmed using differential scanning calorimetry, powder X-ray diffraction, and Fourier transform infrared. FFA:NIC compaction performance was compared with its coformers. Attachment energies (Eatt) with lowest absolute energy slip planes were calculated from reported crystal structures. Powder Brillouin light scattering was used to measure the mechanical moduli, while macroscopic compression performance was evaluated with “in-die” Heckel and compression energy descriptors. The absolute Eatt were found in the following ascending order: NIC < FFA:NIC < FFA. These materials can be arranged with their increased stiffness as FFA < FFA:NIC < NIC based on their elastic moduli. A relatively soft and elastic FFA showed highest compressibility but poor tabletabilit...

Demonstrate the use of a knowledge management and data curation (KProMS) system to support a collaborative research project involving the generation of extensive critical product quality data and the investigation of alternative statistical sampling/analysis strategies for product release. A suite of workflows was developed for the analytical testing and calibration activities associated with the required USP dissolution, HPLC, weight, hardness, and physical dimension measurements. The workflow library also includes the computational steps in the relevant Bayesian and frequentist statistical analyses. The necessary interfaces enabling the transfer of raw data from the instrument output files into KProMS were also implemented. By virtue of a HUB-based implementation of KProMS, all of the details of both laboratory and statistical procedures as well as the resulting data and analysis are web-accessible to all authorized participants. The system enabled data generation, sharing and harvesting over the web, and seamless integration of activities between groups located in three different locations. KProMS can be effectively used in routine management of the dosage form quality data in pharmaceutical operations. This would allow industrial laboratories to seamlessly generate data and populate the knowledgebase to track the analysis for product release and for correlation to process control charting.

Gabapentin was used as a model pharmaceutical compound with susceptibility to polymorphic transformation as a function of environmental and mechanical stress. The utility of 13 C CP/MAS NMR and XRPD as stability-indicating methods to quantify polymorphic transformation kinetics was investigated. Polymorphic Form II and III were distinguishable based on their chemical shift and distinct diffraction peak differences. Reproducible and accurate quantification of polymorphic composition in the presence of selected excipients was demonstrated using both signals from 13 C CP/MAS NMR spectra and XRPD patterns. The effect of excipients on polymorphic transformations (Form II → III) was determined by measuring the transformation after co-milling. Both 13 C CP/MAS NMR and XRPD were capable of measuring polymorphic composition in co-milled excipient mixtures without excipient peak interference. The amounts of Form III present in co-milled mixtures containing colloidal silicon dioxide, starch, hydroxy propyl cellulose and dibasic calcium phosphate were 8.7, 21, 33, and 39 mol%, respectively. A quenching procedure for obtaining 13 C CP/MAS NMR spectra and environmentally-controlled XRPD were devised to determine polymorphic transformation kinetics of co-milled excipient mixtures during storage.

Aerosol delivery of chemotherapeutic nanocarriers represents a promising alternative for lung cancer therapy. This study optimized gemcitabine (Gem)-loaded gelatin nanocarriers (GNCs) cross-linked with genipin (Gem-GNCs) to evaluate their potential for nebulized lung cancer treatment.Gem-GNCs were prepared by two-step desolvation and optimized through Taguchi design and characterized for physicochemical properties. Particle size and morphology were confirmed by scanning and transmission electron microscopy. In vitro release of Gem from Gem-GNCs performed in Dulbecco's phosphate-buffered saline and simulated lung fluid was evaluated to determine release mechanisms. Particle size stability was assessed under varying pH. Differential scanning calorimetry and powder X-ray diffraction were used to determine the presence and stability of Gem-GNC components and amorphization of Gem, respectively. Gem-GNC efficacy within A549 and H460 cells was evaluated using MTT assays. Mucus rheology upon treatment with Gem-GNCs, lactose, and normal saline control was measured. Andersen cascade impaction identified the aerodynamic particle size distribution of the nebulized formulation.Gem-GNCs had particle size, zeta potential, entrapment efficiency, and loading efficiency of 178 ± 7.1 nm, -18.9 mV, 92.5%, and 9.1%, respectively. The Gem and formulation excipients where molecularly dispersed and configured amorphously. Gem-GNCs were stable at pH 5.4-7.4 for 72 hours. Gem release from Gem-GNCs was governed by non-Fickian controlled release due to diffusion/erosion from a matrix-based nanocarrier. Gem-GNCs elicited a 40% reduction of the complex viscosity η*(1 Hz) of human bronchial epithelial cell mucus containing 3 wt% solids to mimic mild airway disease. The nebulized Gem-GNCs had a mass median aerodynamic diameter (MMAD) of 2.0 ± 0.16 μm, geometric standard deviation (GSD) of 2.7 ± 0.16, and fine particle fraction (FPF) of 75.2% ± 2.4%. The Gem-GNC formulation did not outperform the Gem solution in A549 cells. However, in H460, Gem-GNCs outperformed the Gem IC50 reduction by ∼5-fold at 48 and 10-fold 72 hours.Stable, effective, and sustained-release Gem-GNCs were developed. The nebulized Gem-GNCs had satisfactory MMAD, GSD, and FPF and the formulation reduced the dynamic complex viscosity of mucus consistent with increased mobility of nanoparticles.

We present a novel simulation-based investigation of the nucleation of nanodroplets from solution and from vapor. Nucleation is difficult to measure or model accurately, and predicting when nucleation should occur remains an open problem. Of specific interest is the "metastable limit", the observed concentration at which nucleation occurs spontaneously, which cannot currently be estimated a priori. To investigate the nucleation process, we employ gauge-cell Monte Carlo simulations to target spontaneous nucleation and measure thermodynamic properties of the system at nucleation. Our results reveal a widespread correlation over 5 orders of magnitude of solubilities, in which the metastable limit depends exclusively on solubility and the number density of generated nuclei. This three-way correlation is independent of other parameters, including intermolecular interactions, temperature, molecular structure, system composition, and the structure of the formed nuclei. Our results have great potential to further the prediction of nucleation events using easily measurable solute properties alone and to open new doors for further investigation.

Drug-drug cocrystals (DDC) represent a unique subset of pharmaceutical materials offering distinct advantages in combination therapies, pharmacokinetics, and patient compliance. However, their structure-function relationships are rarely reported despite its central importance in successful medicine. A material-sparing approach consisting of a molecular and structural perspective is reported to evaluate tabletability of a model DDC, metformin:salicylic acid, relative to its components: metformin HCl (MET) and sodium salicylate (SAL). MET alone displayed a very poor tabletability, which could be attributed to its isotropic and stiff interaction topology. SAL displayed a highly anisotropic interaction topology with layers of strongly hydrogen-bonded salicylate molecules promoting deformation and tabletability. This is also confirmed by its low moduli. DDC yielded intermediate stiffness and elastic anisotropy material with an improved plastic flow and overall better tabletability. Overall, DDC is a promising therapeutic class requiring the physical-mechanical evaluation to assure their processability to enjoy their therapeutic advantages.

A present investigation aimed for multivariate modeling as a solution to resolve inaccuracy in dissolution testing experienced in the use of in-situ UV fiber optics dissolution systems (FODS) due to signal saturation problems. This problem is specifically encountered with high absorbance of moderate to high dose formulations. A high absorbance not only impede a real-time assessment but can also result in inaccurate dissolution profiles. Full spectra (F) and low absorbance regions (L) were employed to develop linear and quadratic (Q) partial least squares (PLS) and principal component regression (PCR) models. The conventional dissolution of atenolol, ibuprofen, and metformin HCl immediate-release (IR) tablets followed by HPLC analysis was used as a reference method to gauge multivariate models' performance in the 'built-in' Opt-Diss model. The linear multivariate modeling outputs resulted in accurate dissolution profiles, despite the potentially high UV signal saturation at later time points. Conversely, the 'built-in' Opt-Diss model and multivariate quadratic models failed to predict dissolution profiles accurately. The current studies show a good agreement in the predictions across both low absorbance region and full spectra, demonstrating the multivariate models' robust predictability. Overall, linear PLS and PCR models showed statistically similar results, which demonstrated their applicative flexibility for using FODS despite signal saturation and provides a unique alternative to traditional and labor-intensive UV or HPLC dissolution testing.

Currently, there is no systematic approach available for the validation, quantitative assessment, and troubleshooting for the in-situ fiber optic/bathless dissolution system (FODS). In this report, a dissolution protocol was developed and validated for a model product, chlorpheniramine maleate (CPM) 4 mg IR tablets. Dissolution runs were conducted at 37 ± 0.2 °C using a USP apparatus II, at 50 rpm in 500 mL of 0.01 N hydrochloric acid. The dissolution system was validated for linearity, accuracy, precision, specificity, and robustness analogously to an HPLC method validation. The linearity determination method was developed using five concentration levels between 25-125 % of the expected concentration, while for accuracy, 80 %, 100 %, and 120 % levels were used, and precision was determined using six runs at the 100 % level. Probe sampling depth, orientation, analytical wavelength, and paddle speed were varied to evaluate the robustness of the system tested. Method equivalence was established by comparing the dissolution results from FODS and the traditional dissolution method using UV spectrophotometry. Based on the statistics generated using the dissolution tests, the results are linear, accurate, precise, and specific. Robustness testing demonstrates that small changes in operating conditions did not significantly change the result. No significant difference in the amount dissolved at Q-timepoint was observed between FODS and traditional testing. Therefore, the FODS is a suitable alternative to traditional dissolution for CPM immediate-release tablets (many other drug products have been tested in the laboratory, and reports are in preparation). Additionally, the current work discusses problems related to media preparation, probe sensitivity, and excipient effects on data collected using FODS. The instrument-specific artifacts and data analysis problems are addressed and troubleshooting with possible solutions to eliminate or mitigate the errors. Although the FODS method was developed and evaluated using CPM in 500 mL dissolution volume, the dissolution method using a more common pharmacopoeial dissolution volume, i.e., 900 mL, was used to demonstrate the troubleshooting experiments for the drug products requiring 900 mL dissolution media.

Biorelevant media are increasingly being employed as dissolution media in drug development, including in smaller volumes than 900ml and under non-sink conditions. The objectives were to assess interday repeatability, interanalyst repeatability, and interlaboratory reproducibility of dissolution profiles from biorelevant media, as well as to assess the impacts of biorelevant media production method and biorelevant medium volume on dissolution profiles. Ibuprofen and ketoconazole tablets were subjected to dissolution testing in 500ml, 300ml, and 40ml of fasted state simulated gastric fluid (FaSSGF), fed state simulated gastric fluid (FeSSGF), fasted state simulated intestinal fluid version 2 (FaSSIF-V2), and fed state simulated intestinal fluid version 2 (FeSSIF-V2). f2 was used to assess repeatability and reproducibility of dissolution profiles. Results indicate favorable interday repeatability (83 of 88 comparisons were similar), favorable interanalyst repeatability (19 of 21 comparisons were similar), and favorable interlaboratory reproducibility (10 of 14 comparisons were similar) of dissolution profiles from biorelevant media, with commercial media showing greater interlaboratory reproducibility than 'from scratch' media. However, biorelevant medium production had low impact on profiles when one analyst conducted all medium preparations and study procedures at one location. Additionally, biorelevant media detected differences when products were not similar. Overall, biorelevant media showed favorable repeatability and reproducibility performance.

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.

In this work we develop a Bayesian framework for building surrogate stochastic models of complex multi-step processes for which tractable mechanistic models are difficult to construct. The probabilistic process envelope defined by the design space provides an extra level of assurance of product quality over and above that provided by traditional process control. While the application we report is specific to drug products manufactured using traditional batch processing, the proposed framework is applicable in general to batch and continuous manufacturing of products that must meet a set of critical product quality specifications.

Levothyroxine sodium pentahydrate (LEVO) tablets have been on the US market since the mid-twentieth century and remain the most highly prescribed product. Unfortunately, levothyroxine sodium tablets have also been one of the most highly recalled products due to potency and dissolution failures on stability. In 2008, the assay limits were tightened, yet the recalls did not decline, which highlights the serious quality concerns remaining to be elucidated. The aim of the present investigation was to test the hypothesis that the solid-state physical instability of LEVO precedes the chemical instability leading to product failure. The failure mode was hypothesized to be the dehydration of the crystal hydrate, when exposed to certain humidity and temperature conditions, followed by the oxidation of the API through vacated channels. It was previously reported by the authors that LEVO degradation occurred in the presence of oxygen at a low relative humidity (RH). Furthermore, powder X-ray diffractometry shows changes in the crystal lattice of LEVO initially and through the dehydration stages. Storage of LEVO at RT and 40 °C at 4-6% RH for 12 days shows a decrease in d-spacing of the (00 l) planes. Based on a structure solution from the powder data of the dehydrated material, the basic packing motif persists to varying degrees even when fully dehydrated along with disordering. Therefore, the crystal structure changes of LEVO depend on RH and temperature and are now explicable at the structural level for the first time. This exemplifies the dire need for "new prior knowledge" in generic product development.

In this work, a novel risk-based methodology for lot release is proposed. Its objective is to assess the risk that a lot declared to have passed truly meets product specifications. The methodology consists of 3 parts: adaptive sample size determination, estimation of the probability that the product was within specifications, and the lot-release decision. The methodology provides a probabilistic statement about the true quality of the batch. Having a probability estimate is the essential condition of risk-based decision-making. We demonstrate the proposed methodology on experimental data generated from 17 immediate-release solid oral drug products from a number of different manufacturers with 5 to 10 lots per manufacturer.

To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process. Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules. Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form. By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

The purpose of the research described herein was to develop a kinetic model for quantifying the effects of conditional and compositional variations on non-covalent polymorphic and covalent chemical transformations of gabapentin. Kinetic models that describe the relationship between polymorphs and degradation product in a series of sequential or parallel steps were devised based on analysis of the resultant concentration time profiles. Model parameters were estimated using non-linear regression and Bayesian methods and evaluated in terms of their quantitative relationship to compositional and conditional variations. The model was constructed in which co-milling gabapentin with excipients determined three physically-initial concentrations (II0*, II0 and III0) and one chemically-initial concentration (lactam0). For chemical transitions, no humidity effect was present but the catalytic effects of excipients on the conversion of II and III➔lactam were observed. For physical transition, excipient primarily influenced the physical state transition of III➔II through its ability to interact with humidity. This model was shown to be robust to quantitatively account for the effects of temperature, humidity and excipient on rate constants associated with kinetics for each physical and chemical transition.

Release of manufactured lots is a major decision point in reaching the goal of a customer – the product quality is reasonably good – and of manufacture – no rework/scrap/lost revenue. In this study we will focus on pharmaceutical industry (solid dosage form). Adaptive Bayesian sample size determination. In this study we used adaptive Bayesian approach to determine the number of lots needed to estimate inter/intra lot variability. This was dictated by limited number of lots available in the study. Specifically, a linear random effects model was built and fitted to tablet data from multiple lots. The estimate was considered accurate enough when change in signal (or variability estimates) disappeared within noise. In our case we considered 1% of label claim as noise level. However, if signal to noise ratio was high, additional lot was sampled. Sampling included traditional content uniformity and dissolution testing. In order to be consistent with pharmacopeia 10 tablets from a lot were used for content uniformity testing while 12 tablets from the same lot were used for dissolution testing. Manufacturer, however, may not need this step since historical production information may be used to estimate the inter/intra lot variability by employing Bayesian methodology. It is important to note that analytical variability component was factored out which is not easily done with traditional frequentist methodology. Estimation of probability that product is within specifications at given confidence level. The next step was to estimate the probability of product being within specifications at a given confidence level which is metrics used for lot release by ASTM E2709–12 standard. However, the approach delineated in the standard was extended by Bayesian treatment. Specifically, inter/intra lot variability estimates were used to determine the probability while confidence level was replaced by the Bayesian credible interval concept. As delineated in ASTM E2709–12 standard this non-trivial task using frequentist methodology was very straightforward when using Bayesian methodology. We propose that lot can be released (consistently with ASTM E2709–12 standard) when the probability of product being within specifications at a given confidence level is high enough not to cause any harm to the patient. In order to determine the probability threshold, we propose to perform virtual clinical study with Simcyp or PK-Sim to determine if there is no harm to the patient and drug product is efficacious, i.e. drug plasma levels are within therapeutic window for prescribed dosing regimen. We verified the proposed methodology on seven immediate release products from different manufactures. We found that there are large differences in inter/intra lot variability between different manufacturers. Based on our experience more than six lots are typically required to establish accurate variability estimate. The current pharmacopeia doesn’t incorporate inter lot variability and therefore our proposed approach is more restrictive in the sense that it allows releasing lots that contain safer and more efficacious product than using existing lot release criteria. It is based on FDA’s risk based approach. From manufacturers perspective it supports the FDA’s quality metrics initiative to assure that only safe and quality medicine is being produced. While this study considered solid dosage form the proposed methodology could be easily generalized for different dosage forms and any batch processing industries.

Gabapentin was used as a model pharmaceutical compound with susceptibility to polymorphic transformation as a function of environmental and mechanical stress. The utility of

Since 2009, the Korea Meteorological Administration (KMA) has participated in ground validation (GV) projects through international partnerships within the framework of the Global Precipitation Measurement (GPM) Mission. The goal of this work is to assess the reliability of ground-based measurements in the Korean Peninsula as a means for validating precipitation products retrieved from satellite microwave sensors, with an emphasis on East Asian precipitation. KMA has a well-developed operational weather service infrastructure composed of meteorological radars, a dense rain gauge network, and automated weather stations. Measurements from these systems, including data from four ground-based radars (GRs), were combined with satellite data from the Tropical Rainfall Measuring Mission (TRMM) precipitation radar (PR) and used as a proxy for GPM GV over the Korean Peninsula. A time series of mean reflectivity differences (GR − PR) for stratiform-only and above-brightband-only data showed that the time-averaged difference fell between −2.0 and +1.0 dBZ for the four GRs used in this study. Site-specific adjustments for these relative mean biases were applied to GR reflectivities, and detailed statistical comparisons of reflectivity and rain rate between PR and bias-adjusted GR were carried out. In rain-rate comparisons, surface rain from the TRMM Microwave Imager (TMI) and the rain gauges were added and the results varied according to rain type. Bias correction has had a positive effect on GR rain rate comparing with PR and gauge rain rates. This study confirmed advance preparation for GPM GV system was optimized on the Korean Peninsula using the official framework.

The aim of this investigation was to develop and evaluate freeze-dried mannosylated liposomes for the targeted delivery of selenium. Dipalmitoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol were dissolved in a chloroform and methanol mixture and allowed to form a thin film within a rotatory evaporator. This thin film was hydrated with a sodium selenite (5.8 μM) solution to form multilamellar vesicles and homogenized under high pressure to yield unilamellar nanoliposomes. Se-loaded nanoliposomes were mannosylated by 0.1% w/v mannosamine (Man-Lip-Se) prior to being lyophilized. Mannosamine concentration was optimized with cellular uptake studies in M receptor expressing cells. Non-lyophilized and lyophilized Man-Lip-Se were characterized for size, zeta potential, and entrapment efficiency. The influence of liposomal composition on the characteristics of Man-Lip-Se were evaluated using acidic and basic medium for 24 h. Thermal analysis and powder X-ray diffraction were used to determine the interaction of components within the Man-Lip-Se. The size, zeta potential and entrapment efficiency of the optimum Man-Lip-Se were observed to be 158 ± 28.9 nm, 33.21 ± 0.89 mV, and 77.27 ± 2.34%, respectively. An in vitro Se release of 70–75% up to 24 h in PBS pH 6.8 and

As with human beings, dogs suffer from the consequences of cancer. We investigated the potential of a formulation comprised of resveratrol, ellagic acid, genistein, curcumin and quercetin to modulate biomarkers indicative of disease prevention. Dog biscuits were evaluated for palatability and ability to deliver the chemopreventive agents. The extent of endogenous DNA damage in peripheral blood lymphocytes from dogs given the dietary supplement or placebo showed no change. However, H2O2-inducible DNA damage was significantly decreased after consumption of the supplement. The expression of 11 of 84 genes related to oxidative stress was altered. Hematological parameters remained in the reference range. The concept of chemoprevention for the explicit benefit of the canine is compelling since dogs are an important part of our culture. Our results establish a proof-of-principle and provide a framework for improving the health and well-being of “man’s best friend”.

William Penn left no direct testimony to the sources of his intellectual and theological development. Through an investigation of the possible influences on Penn up to when he wrote the majority of...

Fusing complex data from two disparate sources has been demonstrated to improve the accuracy in quantifying active ingredients in mixtures of pharmaceutical powders. A four-component simplex-centroid design was used to prepare blended powder mixtures of acetaminophen, caffeine, aspirin and ibuprofen. The blends were analyzed by Fourier transform infra-red spectroscopy (FTIR) and powder X-ray diffraction (PXRD). The FTIR and PXRD data were preprocessed and combined using two different data fusion methods: fusion of preprocessed data (FPD) and fusion of principal component scores (FPCS). A partial least square (PLS) model built on the FPD did not improve the root mean square error of prediction. However, a PLS model built on the FPCS yielded better accuracy prediction than PLS models built on individual FTIR and PXRD data sets. The improvement in prediction accuracy of the FPCS may be attributed to the removal of noise and data reduction associated with using PCA as a preprocessing tool. The present approach demonstrates the usefulness of data fusion for the information management of large data sets from disparate sources.

Understanding the properties and behavior of pharmaceutical materials is critical to the design of a safe and effective dosage form. The desired performance of pharmaceutical products differs from other areas of engineered material products. With pharmaceutical products, there is an increased level of importance on solubility, dissolution and stability; while a secondary level of importance is given to mechanical properties. The use of multi-scale process understanding suggests incorporating data from the different scales (particle, powder, and dosage form) into a single informatics database. The properties of the active pharmaceutical ingredient and the excipients must be interrogated at each scale. At the particle level, the primary concerns are with solubility, dissolution rate, the anisotropic properties of pharmaceutical crystals, polymorphism and the degree of crystallinity. At the level of the powder scale, the primary concerns are powder flow and the ability of the bulk powder to be compacted into a dosage form. Finally, at the dosage form level, critical issues include the effect of excipient crystallinity on dosage form dissolution rate and the tensile strength of compacts made from milled, roller compacted ribbons. Examples of existing and emerging approaches for understanding these properties and behaviors at each scale are illustrated as key elements in developing a multi-scale process understanding of a pharmaceutical process.

In reality, no crystal is perfect. Crystals bear defects both in the bulk and on the surface. The purpose of this project is to study the correlation between crystal defect density and reactivity of physical transformation. The hypothesis is that larger crystals have the opportunity to pick up more defects during crystal growth than smaller crystals, therefore, have higher reactivity. Flufenamic acid (FFA) was used as a model compound. Phase transformation of crystal Form I (white) to Form III (yellow) of FFA was studied, and observed that larger crystals of FFA Form I transform faster. Furthermore, the etching pits identified on the major crystal faces (1 0 0) using atomic form microscopy (AFM) also showed that larger crystals had higher surface defect density than smaller ones, which correlates with the finding that larger crystals transforms faster than smaller ones. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3839–3848, 2010

As described in this Supplement and elsewhere, consumption of grapes or grape products has been associated with various health benefits. Resveratrol is a unique component of grapes. Following our report on potential cancer chemopreventive activity, thousands of studies have been performed to characterize the mode of action of this substance. Nonetheless, scores of additional chemicals are known to be constituents of grapes, several of which are capable of mediating biological responses. Accordingly, when considering grapes and health, a holistic view appears to be more meaningful, taking into account all chemical components, metabolism, biological potential, biodistribution, absorption, processing, etc. To fathom such a massive amount of information, we propose the creation of focused ontologies. Grapes seem reasonable as a test bed for exploring this approach, especially because a fair amount of results are available with whole-grape powder. In essence, by utilizing a next generation intelligent system, attempts can be made to leverage the existing complexity. This approach involves bringing together all available information, together with expert judgment, and processing this information through a computational "engine" or engines to provide suggested solutions (or implicit functional relationships). Accomplishment of this task, employing grapes as a prototype, could lead to broader application by incorporating the myriad of features associated with other fruits and vegetables. The ability to correlate heretofore-uncharacterized "signatures" with biologic outcome could fundamentally transform copious amounts of disparate information into a coherent explanation of human disease prevention.

The purpose of this research is to study the use of Ea as a measure of the energy barrier to the solid-state desolvation of two indomethacin solvates: tert-butyl alcohol (TBA) solvate and methanolate. The desolvation of these solvates was studied over a range of temperatures (60−120 °C) by isothermal thermogravimetric analysis. Intimately mixing 15% α and γ seeds with the two solvates was carried out in order to assess the effect of seeding/nucleation on desolvation. The results suggest that solid-state desolvation predominantly proceeded by a nucleation-limited mechanism as described by the Avrami−Erofeev kinetics equation. On the basis of the equation, an “isokinetic” range was identified between 60−80 °C for the methanolate and 60−90 °C for the TBA solvate, and the dominant mechanism of desolvation remained unchanged. The Arrhenius activation energies (Ea) were 27.9 and 16.6 kcal/mol for the methanol and TBA solvates, respectively. In the “isokinetic” range, Ea values of 36.9 and 15.5 kcal/mol, respect...

Powder shear testing has been used to assess flowability of powders for at least 48 years [A.W. Jenike, Storage and Flow of Solids, Bull., Eng. Exp. Station, Univ. Utah, vol. 123, 1964]. A fundamental part of the data interpretation involves construction of Mohr’s circles such that they are tangent to the experimental locus; a set of powder shear strengths, τm, measured at variable applied compressive normal stresses, σN. Despite the customary application of this tangency criterion, we have found justifications for it to be scant. In this work, we revisit the Mohr’s circle construction and find that proper construction would require measurement of reactionary lateral powder stresses, σr. We further provide reasoning to support placement of the experimental locus passing through the apex (top) of Mohr’s circles for isotropic or orthotropic powders and not tangentially to them. This placement is not unexpectedly in agreement with the results of a recent numerical simulation [C. Thornton, L. Zhang, Numerical simulations of the direct shear test, Chem. Eng. Technol. 26 (2) (2003) 153–156], and reveals errors in subsequently calculated constants on the order of 20%.

Orotic acid (OTA) is reported to exist in the anhydrous (AH), monohydrate (Hy1), and dimethyl sulfoxide monosolvate (SDMSO) forms. In this study we investigate the (de)hydration/desolvation behavior, aiming at an understanding of the elusive structural features of anhydrous OTA by a combination of experimental and computational techniques, namely, thermal analytical methods, gravimetric moisture (de)sorption studies, water activity measurements, X-ray powder diffraction, spectroscopy (vibrational, solid-state NMR), crystal energy landscape, and chemical shift calculations. The Hy1 is a highly stable hydrate, which dissociates above 135 °C and loses only a small part of the water when stored over desiccants (25 °C) for more than one year. In Hy1, orotic acid and water molecules are linked by strong hydrogen bonds in nearly perfectly planar arranged stacked layers. The layers are spaced by 3.1 Å and not linked via hydrogen bonds. Upon dehydration the X-ray powder diffraction and solid-state NMR peaks become broader, indicating some disorder in the anhydrous form. The Hy1 stacking reflection (122) is maintained, suggesting that the OTA molecules are still arranged in stacked layers in the dehydration product. Desolvation of SDMSO, a nonlayer structure, results in the same AH phase as observed upon dehydrating Hy1. Depending on the desolvation conditions, different levels of order–disorder of layers present in anhydrous OTA are observed, which is also suggested by the computed low energy crystal structures. These structures provide models for stacking faults as intergrowth of different layers is possible. The variability in anhydrate crystals is of practical concern as it affects the moisture dependent stability of AH with respect to hydration.

This work is an extension of the earlier work from this laboratory aimed at identifying raw material properties critical to the modeling of granule and ribbon properties as part of the optimization of roller (RC) compaction processes. The utility of roll gap (RG) and near-infrared (NIR) signal, specifically, the spectral slope, as process critical control parameters (PCCPs) was also evaluated. Raw material tabletability, particle size, size distribution span, and tapped density were found to be most important factors for building robust predictive models. RG and NIR spectral slope in combination with RC operating parameters yielded models with good predictability for RC responses. Our results support the suitability of RG and NIR spectral slope as PCCPs in roller compaction, specifically, through ribbon density monitoring.

To study how polymeric additives interact with the crystal surface of acetaminophen, and why they have different effects on drug crystallization and dissolution.The effects of different polymers on the etching patterns, crystallization and intrinsic dissolution rate (IDR) of acetaminophen have been studied.Some polymers have shown clear consistency in their effects on the etching patterns, crystallization and IDR of acetaminophen. For example, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidone (PVP), not only changed the etching patterns of the acetaminophen (010) face, but also inhibited acetaminophen crystallization significantly. Some polymers, like 2-hydroxyethyl cellulose (HEC), poly(vinyl alcohol) (PVA) and poly(ethylene glycol) (PEG) only had limited effects on the IDR and etching patterns, and no significant inhibitory effects on crystallization.Even though some polymeric additives have no structural similarity to acetaminophen, they still can affect dissolution and crystallization of acetaminophen due to the synergic effects of their neighboring subunits during surface adsorption. The effects of polymeric additives on crystallization and dissolution of acetaminophen are affected not only by the specific interactions between adsorbed polymer molecules and crystal surface, but also by the mobility of the functional groups involved in the specific interactions.

Binary mixtures of pharmaceutically relevant powders were investigated using dielectric spectroscopy over a frequency range of 10 −3 to 300 kHz. Two different binary mixtures were studied as a function of concentration; pseudoephedrine hydrochloride in dicalcium phosphate dihydrate and acetaminophen in microcrystalline cellulose, respectively. Dielectric properties obtained from measurements of these systems are reported and found to follow a trend similar to the observed triboelectric behavior after low-shear tumble blending. Powder samples for charge measurement were mixed using a stainless steel blender and dispensed directly into a Faraday pail. For the two binary mixtures studied, low-frequency conductivity calculated from the imaginary part of the complex permittivity (or loss factor) was observed to be sensitive to water content. Furthermore, the unanticipated trends previously reported in the measured specific charge after blending were observed to correspond with the surface charge density calculated from the capacitance of the composite material. The implications of moisture and the physical and chemical properties of these dielectric mixtures are also discussed with supporting results.

Elucidation of the mechanisms for mechanically activated phase transformations of API are necessary for progress in materials and process understanding. The mechanically induced solid-state transformation between the A and C enantiotropes of the anti-diabetic drug chlorpropamide (C 10 H 13 ClN 2 O 3 S) was investigated. The structure of the high temperature stable phase (form C) was solved using powder X-ray data. Transmission powder X-ray diffraction (PXRD) and Raman spectroscopy were used for in situ quantification and analysis of the phase interconversion that occurs as a function of applied pressure during compaction. Each polymorph was observed to undergo a solid-state transition, which increased with pressure to a maximum extent that corresponded with the consolidation limit of the respective bulk powder. Neither form was observed to convert under hydrostatic pressure, suggesting a shear dependence for interconversion at compaction pressures. Examination of the two crystallographic structures indicated that both forms have a common slip system and preserved molecular positions. It is suggested that the transformation of either form is allowed when resolved shear stresses initiate deformation, causing lattice distortion, which allows the simultaneous reconformation of molecules.

The effects of PURE-DENT® and SPRESS® starch properties on their compression behavior was characterized using "SM(2) " approach (structural properties, macroscopic properties, and multivariate analysis). Moisture sorption rate constants, moisture content, amylose and amylopectin degradation enthalpy, percent crystallinity, amylose-amylopectin ratio, and cross-linking degree were used to profile starch structural properties. Particle density, particle size distribution, and Heckel compression descriptors [yield pressure (YP) of plastic deformation, and elastic recovery] were used as macroscopic descriptors. The structural and macroscopic properties were correlated qualitatively [principal component analysis (PCA)] and quantitatively [standard least square regression (SLSR)] with the tablet mechanical strength (TMS). These analyses revealed that the differences correlated with amylose-amylopectin content, particle density, compression mechanisms, and TMS between the starch grades. Univariate analysis proved lacking; however, PCA identified the particle size, moisture content, percent crystallinity, amylose-amylopectin ratio, and YP of plastic deformation and elastic recovery as the main factors influencing the starch TMS. SLSR quantified the positive influence of Fourier transform infrared spectra absorbance ratio at 1022-1003 and YP of the immediate elastic recovery, and the negative contribution of amylopectin content on the TMS. Therefore, starch amylose and amylopectin content, crystallinity, and lower elastic recovery are mainly responsible for better TMS.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.