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Data integrity (DI) reaffirms the pharmaceutical industry's commitment to manufacture drugs that are safe, effective and fulfil quality standards. At the same time, DI is a crucial tool for regulatory authorities to use in protecting public health. Recent FDA Form-483 observations and warning letters indicate that DI is the main issue the pharmaceutical industry is currently dealing with. Failure to comply with DI requirements may result in a high number of un-validated results, which may cause post-marketing issues and frequent product recalls. To address the underlying causes of DI problems, a comprehensive approach is necessary. The majority of DI issues are caused by poor quality culture, organizational or individual behaviour, leadership, processes, or technology. DI should be effectively integrated into the quality management system, and it should apply to both paper and electronic records. Employees should be trained on 21 CFR Part 11. Consistent review and audit are required to ensure that procedures are followed and audit trails are generated. Electronic systems, in addition to being an efficient solution (system integration, data verification at both input and output, security), offer advantages over traditional paper-based systems in terms of improved compliance with DI regulatory requirements. For example, many electronic system platforms provide enhanced security features and audit trail capabilities. Finally, management support for data governance is essential for successful implementation of DI. This article reviews commonly observed deviations by FDA pertaining to DI and discusses measures to be undertaken to avoid them., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Metformin is a widely used first-line oral antidiabetic agent. TheFood and Drug Administration (FDA) confirmed the presence of the ofN-nitrosodimethylamine (NDMA) impurity, a carcinogenic, above the acceptable daily intake (ADI, 96 ng/day) in certain metformin products. The objective of the present study was to assess in-use stability of commercial metformin products for NDMA and dissolution quality attributes. Four immediate-release (M1-M4) and six extended-rerelease (M5-M10) metformin products were evaluated in the stability testing. All products were repacked in pharmacy vials and stored at 30 °C/75% RH for 12 weeks. Five products (M2, M3, M5, M7 and M10) had NDMA level above ADI limit (96 ng/day) before in-use stability exposure. NDMA in M2 (1164 ± 52.9 ng/tablet) and M3 (3776 ± 351.9 ng/tablet) products were 12 and 39 folds of ADI, respectively. Similarly, ER products, M5 (191 ± 94.1 ng/tablet), M7 (1473 ± 47.3 ng/tablet) and M10 (423 ± 55.8 ng/tablet) exhibited NDMA of 1.9, 15.3 and 4.4 folds of ADI, respectively. The impurity level significantly (p < 0.05) increased after 12-week stability exposure to 2.72, 2.47, 2.23 and 2.78 folds of initial values in M2, M3, M7 and M10. In summary, these findings suggested that carcinogenic impurity generation was affected by in-use stability condition exposure and it is expected that several more products currently in the market may also be recalled soon., (Copyright © 2022. Published by Elsevier B.V.)

The focus of present work was to characterize ultra-long acting prodrug of dolutegravir (DTG) and develop biodegradable microparticle formulation. Palmitic acid (PA) conjugated prodrug of DTG was prepared by esterification of hydroxyl group of DTG with the carboxyl group of PA. Physicochemical properties of the prodrug was characterize by MS, NMR, FTIR, SEM, DSC, NIR-CI, pH-solubility, and solid and liquid pH-stability. Comparative solid and liquid stability was performed by storing powder DTG and DTG-Palmitate at 40 °C/75% RH for three months and liquid solution pH 2-8 at room temperature for 24 h, respectively. Pharmacokinetic evaluation was performed in white albino New Zealand rabbits by subcutaneous injection (30 mg/Kg). Poly(lactide-co-glycolide) microparticle formulation was prepared by emulsification-evaporation method and characterized for particle size distribution, shape, drug loading and in-vitro release. MS, NMR, FTIR, SEM, DSC, NIR-CI indicated formation of prodrug. Melting point of the prodrug was lower than DTG but higher than PA. Shape of DTG crystals was irregular while DTG-Palmitate crystals was fine-needle. Solid and liquid stability profiles of the prodrug were similar to DTG. Plasma half-life, area under the curve, and mean-residence time of DTG-Palmitate were 8.8, 2.3 and 14.7 folds of DTG. D 90 of DTG and DTG-Palmitate microparticles was 107.1 ± 2.7 and 94.3 ± 3.4 µm, respectively. The in-vitro drug release was almost complete in three weeks from DTG microparticles while it was <85% in six months from DTG-Palmitate microparticles. In conclusion, physicochemical and pharmacokinetic properties and biodegradable microparticles of the prodrug suggested that the prodrug has potential of sustaining DTG release for ultra-long period compared to DTG., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study aimed to improve the dissolution of the poorly soluble drug lopinavir (LPV) by preparing amorphous solid dispersions (ASDs) using solvent evaporation method. The ASD formulations were prepared with ternary mixtures of LPV, Eudragit® E100, and microcrystalline cellulose (MCC) at various weight ratios. The ASDs were subjected to solid-state characterization and in vitro drug dissolution testing. Chemometric models based on near infrared spectroscopy (NIR) and NIR-hyperspectroscopy (NIR-H) data were developed using the partial least squares (PLS) regression and externally validated to estimate the percent of the crystalline LPV in the ASD. Initially, the solid-state characterization data of ASDs showed transformation of the drug from crystalline to amorphous. Negligible fraction of crystalline LPV was present in the ASD (3%). Compared to pure LPV, ASDs showed faster and higher drug dissolution (<2% vs. 60.3-73.5%) in the first 15 min of testing. The ASD was stable against crystallization during stability testing at 40 °C/75% for a month. In conclusion, the prepared ASD was stable against devitrification and enhance the dissolution of LPV., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The objectives of this study were to develop and characterize amorphous lopinavir (LPV) printlets and to the quantify crystalline fraction of LPV in the printlets by X-ray powder diffraction (XRPD)-chemometric models. Amorphous printlets (4.5 mm diameter × 3 mm height) of various LPV concentrations were fabricated by selective laser sintering (SLS) 3D technique. The printlets were characterized for physicochemical properties. The XRPD data in conjunction with chemometric method were used to quantify the crystalline fraction of the drug. The LPV content in the printlets was 95.2-100.9%, disintegration time was < 2 min, and dissolution was fast (>90% of LPV was dissolved in < 30 min). The porosity of the printlets increased with an increase in the LPV percentage. The differential scanning calorimetry (DSC) and XRPD data of the printlets demonstrated that the majority of LPV was present in amorphous form. The XRPD-chemometric models showed good linearity and low root mean squared error, standard error, and bias. Models validation showed that the actual values of crystalline and amorphous fractions of the drug were close to the predicted values. These results demonstrated the feasibility of fabricating amorphous printlets by SLS method, and the application of the XRPD-chemometric models to quantify low fractions of crystalline drug in the 3D formulations if they are formed due to process or environment related variables., (Copyright © 2020. Published by Elsevier B.V.)

Rifaximin (RFX) exhibit polymorphism and commercial formulation contains the α form. The polymorphic transformation of the RFX in the drug product have significant effect on the clinical outcome. The focus of present work was to understand effect of formulation component and manufacturing method, and exposure to stability condition on polymorphic stability and dissolution of RFX tablets. The RFX tablets containing 2.5, 5 and 10% glyceryl palmitostearate (GPS) were manufactured by direct-compression and wet-granulation followed by compression. Ethanol was used as a granulating solvent. The tablets were packed in pharmacy vials and exposed to 40 °C/75% RH for four weeks. The tablets were characterized for polymorphic form by X-ray powder diffraction (XRPD) and Fourier infrared spectroscopy (FTIR), assay and dissolution. Before exposure to stability condition, dissolution ranged from 78.0 ± 2.3 to 81.9 ± 3.5%, and 72.7 ± 2.0 and 75.9 ± 5.8% in directly compressed and ethanol-granulated formulations, respectively. GPS amount of 10% caused a decrease in dissolution albeit insignificant (p > 0.05). The polymorphic forms of RFX were α and γ in directly compressed and ethanol-granulated formulations, respectively. There was a decrease in dissolution rate and extent after exposure to 40 °C/75% RH in directly compressed formulations. On the other hand, only dissolution rate was affected in ethanol-granulated formulations. The dissolution ranged from 52.8 ± 2.0 to 70.0 ± 3.0% in directly compressed formulations after four weeks exposure to 40 °C/75% RH exposure. A decrease in dissolution was linked to polymorphic transformation of the drug and GPS in the formulations after exposure to stability condition. XRPD and FTIR data indicated α to β transformation in directly compressed formulations while no polymorphic change was observed in ethanol-granulated formulations. In conclusion, this study clearly showed effect of formulation and manufacturing variables, and stability exposure on the polymorphic stability and dissolution of RFX, which may have clinical ramification., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The focus of the study was to understand the effects of formulation and process variables on the printlets quality manufactured by selective laser sintering (SLS) 3D printing. The Box-Behnken response surface methodology was used to evaluate effects of individual variables and combinations thereof. The formulation and process variables studied were printing chamber temperature (°C, X 1 ), laser scanning speed (mm/sec, X 2 ) and lactose monohydrate concentration (%, X 3 ). The responses studied were weight of printlets (mg, Y 1 ), hardness (N, Y 2 ), disintegration time (sec, Y 3 ) and dissolved drug fraction in 15 min (%, Y 4 ). The values of Y 1 , Y 2 , Y 3 and Y 4 varied from 170.2-257.0 mg, 5.5-32.0 N, 20-120 s and 64.4-97.5%, respectively. The studied factors showed statistically significant effects on the dependent variables (p < 0.04). The correlation coefficient between empirical and model predicted values for Y 1 , Y 2 , Y 3 and Y 4 were 0.999, 0.992, 0.998 and 0.983, respectively. The model was validated by an independent experiment and actual values of the responses were in close agreement with model predicted values. Fourier transformed infrared spectroscopy indicated no chemical interactions between the components of the formulation during printing process. X-ray powder diffractograms suggested a decrease in crystallinity of the drug and lactose in the printlets. Chemical images indicated uniform distribution of the drug. Scanning electron microscopy and X-ray micro-CT scanning showed a very porous microstructure of the printlets with a porosity of about 37.89%. In conclusion, the SLS method of manufacturing provides a feasible and flexible avenue for fabricating dosage forms with tailored characteristics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

There has been a long-standing discussion in the scientific literature on the thallium (Tl) binding capacity of ferric hexacyanoferrate (insoluble) and potassium hexacyanoferrate (soluble) forms of Prussian blue (PB). The literature sometime suggests that the soluble form of PB should be used to treat thallium poisoning, instead of the FDA approved insoluble form of PB. The literature debate is further complicated by the lack of fundamental characterization data such as critical quality attributes (CQAs) that clearly define the analog forms. The purpose of this study is to compare, the binding capacity of soluble and insoluble PB analogs with the same CQAs (particle size/distribution and water content). Water content and particle size/particle distribution were determined by TGA, and solid-state laser diffraction particle sizing. Thallium binding studies were conducted at physiological pH to determine the maximal binding capacity (MBC) at equilibrium. Multiple linear regression and principal component analysis was also used for multivariate data analysis. Results indicate that insoluble and soluble analogs, with similar quality attributes, have nearly identical, MBC binding capacities of (441.5 mg/g) for insoluble vs soluble (458.4 mg/g). However, when both analog forms with different CQAs such as water, particle size were compared, results indicated significantly higher or lower thallium binding levels. In conclusion, it is essential that the FDA approved iron form with well-defined CQAs is used to treat thallium poisoning and radioactive thallium metal contamination for consistent therapeutic outcomes., (Published by Elsevier B.V.)

The focus of this work was to explore feasibility of using blends of cellulose esters (CA 320S, CA 3980-10 or CAB 171-15) and enteric polymers (C-A-P, Eudragit® L100 or HPMCP HP-55) for delayed and enteric coating of tablets containing either diclofenac sodium (DFS, high dose) or prednisone (PDS, low dose) drug. The core tablets of DFS or PDS were coated with polymer blends to achieve approximate weight gain of 5% and 10%. The coated tablets were characterized for dissolution (0.1 N HCl and phosphate buffer pH 6.8) and surface morphology. The surface morphology of CA 398-10 or CAB 171-15 based polymer blends was rough and fibrous. Less than 0.5% drug was dissolved in 120 min from 5% w/w coated tablets in acid-phase dissolution testing. The dissolution in phosphate buffer pH 6.8 medium varied from 16.2 ± 0.2 to 98 ± 2.1%, and 30.1 ± 0.5% to 101.7 ± 3.4% in 120 min from DFS and PDS coated tablets, respectively. Dissolution was less in CA 320S based blends compared to CA 398-10 or CAB 171-15 blends in phosphate buffer medium. Furthermore, there were no significant differences observed in dissolution profiles of coated tablets of DFS or PDS. This can be explained by dose of the drugs. Additionally, dissolution was higher in tablets coated with enteric polymer alone compared with the blends. In conclusion, core tablets can be coated with cellulose ester and enteric polymers blend to impart both delayed and enteric release feature to the tablets containing hydrophilic or hydrophobic drug., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Phenytoin sodium (PS) is a narrow therapeutic index drug that dictates maintenance of narrow plasma concentration of the drug. This requires a good quality product that meets regulatory specifications throughout shelf-life as well as during the usage period. Quality of the drug product may change if not develop in a scientific fashion which may have ramifications on clinical outcome. The focus of the study was to understand the effect of process variables and storage conditions on the disproportionation and phase transformation of the drug, and dissolution of extended-release capsules of PS. Four formulations were prepared to contain either powder blend or granules of PS with commonly used excipients. The granules were prepared in a high shear mixture by granulating with water, ethanol or mixture thereof. The capsules were stored in pharmacy vials for 4-weeks at 40 °C/75% RH and 30 °C/65% RH. Formulations were characterized by spectroscopies (FTIR, NIR, and chemical imaging), X-ray powder diffraction (XRPD), dissolution and assay. Granules filled capsule did not meet USP dissolution specifications and there was a significant decrease in dissolution on exposure to stability conditions. Dissolution decreased from 77.56 ± 3.83% to 42.34 ± 4.31%, and 63.96 ± 6.12 to 46.53 ± 2.91 in physical mixture and water granulated formulations, respectively, after four weeks exposure at 40 °C/75% RH. Spectroscopic (NIR, FTIR, and chemical imaging) data indicated disproportionation of the drug during the storage period. Moreover, XRPD data explained a decrease in dissolution in the initial granules filled capsules as well as temperature and humidity exposed samples. It indicated the phase transformation of the drug and/or excipients, disproportionation and/or interactions. These changes further accelerated on exposure to stability conditions. In conclusion, our studies indicated the significant effect of process variables and stability conditions on the critical quality attributes of PS extended-release capsule that has the potential impact on the clinical performance of the product., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Phenytoin sodium (PS) has a tendency to convert to its base form; phenytoin base (PHT) during manufacturing, packaging, shelf life and in-use conditions that can influence its clinical performance. The objective of the present work was to develop a non-destructive, quick and easy analytical method for quantification of PHT in the drug product. A formulation was prepared to contain the excipients of commercial capsule formulation of PS. The formulation containing either 100% PHT or PS was prepared and these formulations were mixed in different proportion to achieve 0-100% PHT matrices. FTIR, NIR and Raman spectra of samples were collected. Data were truncated and mathematically pretreated before development of partial least squares (PLS) and principal component analysis (PCA) regressions model. The models were assessed by slope, intercept, R, R 2 , root mean square error (RMSE) and standard error (SEP). The models exhibited good linearity over the selected range of PHT in the formulations with low error as indicated by slope that was close to one and small values of intercept, RMSE and SE. The models of NIR based data were more accurate and precise than Raman data based models as indicated by the low values of RMSE and SE. Prediction accuracy of independent samples containing 25% PHT using NIR models were similar to Raman models. On the other hand, the prediction was more precise for the independent sample containing 5% PHT using NIR data based models compared to Raman data based models as indicated by standard deviation. In conclusion, chemometric models based on NIR and Raman spectroscopies provides a fast and easy way to monitor the disproportionation of PS in the drug products., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The objective of the present investigation was to understand the effects of excipients and curing process on the abuse deterrent properties (ADP) of Polyox™ based directly compressible abuse deterrent tablet formulations (ADFs). The excipients investigated were lactose (monohydrate or anhydrous), microcrystalline cellulose and hydroxypropyl methylcellulose. The ADPs studied were tablet crush resistance or hardness, particle size distribution following mechanical manipulation, drug extraction in water and alcohol, syringeability and injectability. Other non-ADPs such as surface morphology and tablet dissolution were also studied. It was found that presence of 50% or more of water soluble or swellable excipient in the ADF tablets significantly affected the tablet hardness, particle size distribution following mechanical manipulation and drug extraction while small amount (5%) of excipients had either minimal or no effect on ADPs of these tablets. Addition of high molecular weight HPMC (K 100M) affected syringeability and injectability of ADF. Curing process was found to affect ADPs (hardness, particle size distribution, drug extraction and syringeability and injectability) when compared with uncured tablet. In conclusion, addition of large amount of excipients, especially water soluble ones in Polyox™ based ADF tablets increase the risk of abuse by various routes of administration., (Published by Elsevier B.V.)

Prescription drug products abuse/misuse is epidemic in United States. Opioids drug forms major portion of prescription drug product abuse. Abuse deterrence formulation (ADF) is one of the many approaches taken by sponsors to tackle this problem. It involves formulating opioids into dosage forms that will be difficult to abuse/misuse. Current investigation focused on evaluating the abuse deterrent properties (ADP) of ADF manufactured by direct compression method. Effect of process and formulation variables on ADP was investigated by statistical design of experiment (fractional factorial design). Independent factors studied were molecular weight of polyethylene oxide (Polyox™), curing time, temperature and method, and antioxidant type. Sotalol hydrochloride was selected as a model drug. ADP investigated were hardness/crush resistance, syringeability and injectability, physical manipulation (reduction into powder) and drug extraction in water and alcohol. Hardness and syringeability are evaluated by newly developed quantitative procedure. Other properties were also investigated such as morphology, crystallinity, assay and dissolution. The hardness and drug extraction was significantly (p<0.05) affected by curing temperature. Formulations could be powdered in 3 min irrespective of their hardness. Syringeability and injectability were intrinsic properties of the polymer used in the formulation, and were not affected by the investigated factors. Crystallinity of the polymer and drug changed, and was dependent upon curing temperature and time. The dissolution and assay were independent of formulation and process parameters studied. In conclusion, the study indicated some advantages of ADF product compared to non-ADF prepared by direct compression. However, the ADF should not be viewed as abuse proof product rather as incrementally improved product., (Published by Elsevier B.V.)

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products., (Published by Elsevier B.V.)

Understanding the impact of pharmaceutical processing, formulation excipients and their interactions on the solid-state transitions of pharmaceutical solids during use and in storage is critical in ensuring consistent product performance. This study reports the effect of polymer viscosity, diluent type, granulation and granulating fluid (water and isopropanol) on the pseudopolymorphic transition of theophylline anhydrous (THA) in controlled release formulations as well as the implications of this transition on critical quality attributes of the tablets. Accordingly, 12 formulations were prepared using a full factorial screening design and monitored over a 3 month period at 40 °C and 75%. Physicochemical characterization revealed a drastic drop in tablet hardness accompanied by a very significant increase in moisture content and swelling of all formulations. Spectroscopic analysis (ssNMR, Raman, NIR and PXRD) indicated conversion of THA to theophylline monohydrate (TMO) in all formulations prepared by aqueous wet granulation in as early as two weeks. Although all freshly prepared formulations contained THA, the hydration-dehydration process induced during aqueous wet granulation hastened the pseudopolymorphic conversion of theophylline during storage through a cascade of events. On the other hand, no solid state transformation was observed in directly compressed formulations and formulations in which isopropanol was employed as a granulating fluid even after the twelve weeks study period. The transition of THA to TMO resulted in a decrease in dissolution while an increase in dissolution was observed in directly compressed and IPA granulated formulation. Consequently, the impact of pseudopolymorphic transition of theophylline on dissolution in controlled release formulations may be the net result of two opposing factors: swelling and softening of the tablets which tend to favor an increase in drug dissolution and hydration of theophylline which decreases the drug dissolution., (Published by Elsevier B.V.)

The availability of in vitro performance tests such as in vitro drug release testing (IVRT) and in vitro permeation testing (IVPT) are critical to comprehensively assure consistent delivery of the active component(s) from semisolid ophthalmic drug products. The objective was to study the impact of drug loading and type of ointment base on the in vitro performance (IVRT and IVPT) of ophthalmic ointments using acyclovir as a model drug candidate. The in vitro drug release for the ointments was evaluated using a modified USP apparatus 2 with Enhancer cells. The transcorneal permeation was carried out using rabbit cornea on modified vertical Franz cells. The drug retention in cornea (DRC) was also determined at the end of transcorneal drug permeation study. The in vitro drug release, transcorneal drug permeation as well as DRC exhibited a proportional increase with increasing drug loading in the ointment. On comparing the in vitro drug release profile with transcorneal permeation profile, it appears that drug release from the ointment is controlling acyclovir transport through the cornea. Furthermore, enhanced in vitro transcorneal permeation relative to the in vitro drug release underscores the importance of the interplay between the physiology of the ocular tissue and ointment formulation. The results indicated that IVRT and IVPT could be used to discriminate the impact of changes in drug load and formulation composition of ophthalmic ointments., (Copyright © 2015. Published by Elsevier B.V.)

Warfarin sodium (WS) is a narrow therapeutic index drug and its product quality should be thoroughly understood and monitored in order to avoid clinical performance issues. This study was focused on understanding the effect of manufacturing and formulation variables on WS product critical quality attributes (CQAs). Eight formulations were developed with lactose monohydrate (LM) or lactose anhydrous (LA), and were either wet granulated or directly compressed. Formulations were granulated either with ethanol, isopropyl alcohol (IPA) and IPA-water mixture (50:50). Formulations were characterized for IPA, water content, hardness, disintegration time (DT), assay, dissolution and drug physical forms (scanning electron microscopy (SEM), near infrared chemical imaging (NIR-CI), X-ray powder diffraction (XRPD) and solid state nuclear magnetic resonance (ssNMR)), and performed accelerated stability studies at 40°C/75% RH for three days. The DT and dissolution of directly compressed formulations were faster than wet granulated formulations. This was due to phase transformation of crystalline drug into its amorphous form as indicated by SEM, NIR-CI, XRPD and ssNMR data which itself act as a binder. Similarly, LM showed faster disintegration and dissolution than LA containing formulations. Stability results indicated an increase in hardness and DT, and a decrease in dissolution rate and extent. This was due to phase transformation of the drug and consolidation with particles' bonding. In conclusion, the CQAs of WS product were significantly affected by manufacturing and formulation variables., (Published by Elsevier B.V.)

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time., (Published by Elsevier B.V.)

Owing to its unique anatomical and physiological functions, ocular surface presents special challenges for both design and performance evaluation of the ophthalmic ointment drug products formulated with a variety of bases. The current investigation was carried out to understand and identify the appropriate in vitro methods suitable for quality and performance evaluation of ophthalmic ointment, and to study the effect of formulation and process variables on its critical quality attributes (CQA). The evaluated critical formulation variables include API initial size, drug percentage, and mineral oil percentage while the critical process parameters include mixing rate, temperature, time and cooling rate. The investigated quality and performance attributes include drug assay, content uniformity, API particle size in ointment, rheological characteristics, in vitro drug release and in vitro transcorneal drug permeation. Using design of experiments (DoE) as well as a novel principle component analysis approach, five of the quality and performance attributes (API particle size, storage modulus of ointment, high shear viscosity of ointment, in vitro drug release constant and in vitro transcorneal drug permeation rate constant) were found to be highly influenced by the formulation, in particular the strength of API, and to a lesser degree by processing variables. Correlating the ocular physiology with the physicochemical characteristics of acyclovir ophthalmic ointment suggested that in vitro quality metrics could be a valuable predictor of its in vivo performance., (Published by Elsevier B.V.)

The objective of this study was to develop and validate XRPD analytical method for the estimation of percent crystalline warfarin sodium present in drug products. Warfarin sodium (WS) is a clathrate containing Isopropyl alcohol entrapped in the crystalline structure. Four types of WS-excipient mixtures were prepared and used to make four formulations: M1 containing lactose monohydrate (WS: excipient 1:9), M2 containing anhydrous lactose (WS: excipient 1:9), M3 containing lactose monohydrate (WS: excipient 1:21.5), M4 containing lactose anhydrous (WS: excipient 1:21.5). Thoroughly mixed powders were packed in the XRD sample holders and diffractogram were collected. Diffractogram in the 7-9 2θ were found to be distinctive as the peak intensity grows with increasing percent crystalline WS. This peak region was, therefore, used to validate the XRPD method. Validation parameters were evaluated for accuracy, precision, linearity, limit of detection (LOD), and limit of quantitation (LOQ). LOD and LOQ for M1, M2, M3, and M4 were 3.04, 3.17, 4.17, 4.49% and 9.21, 9.62, 12.65, 13.30%, respectively. The method was found to be linear with R(2)>0.99. With changing scan speed, X-ray power output, and type of sample holder, the method was found to be robust. Prediction of the % crystalline content of the WS sample with known crystallinity showed close agreement between actual and predicted value. In summary, XRPD method was validated, which can be used as a quantitative method for the estimation of % crystalline WS present in a drug product., (Published by Elsevier B.V.)

The objective of the study was to analyze the effect of controlled and uncontrolled freezing step of a lyophilization process on the extent of non-enzymatic glycation and aggregation of an IgG1 formulation at two concentrations (1mg/ml and 20mg/ml). The degree of glycation (%) was determined through boronate affinity chromatography and its effect on the formation of soluble aggregates and higher molecular weight species was studied using dynamic light scattering (DLS) and size exclusion chromatography with multi-angle light scattering (SEC-MALS). The effect of non-enzymatic glycation on the secondary structure of the formulations was also studied using circular dichroism (CD) spectroscopy and Fourier transform infrared (FT-IR) spectroscopy. Results indicated that controlled nucleation yielded higher residual moisture contents and significantly lower specific surface areas for the two monoclonal antibody concentrations compared with uncontrolled nucleation cycle (p<0.05). For the two concentrations, uncontrolled nucleation resulted in significantly higher levels of glycation compared with controlled nucleation samples (p<0.05). Further, it was observed that higher storage temperatures (25°C/60% RH) versus 5°C resulted in higher glycation. Even though SEC-MALS analyses of the low concentrated formulations did not reveal the formation of higher molecular weight species, DLS analyses at two storage conditions revealed increases in the hydrodynamic radii and polydispersity index of the reconstituted formulations, suggesting the onset of formation of smaller species in the formulations. CD spectroscopy did not reveal any differences in the secondary structure of the mAb for the two concentrations after lyophilization. In conclusion, the freezing step method impacted the extent of glycation in lyophilized samples and the hydrolyzed component of sucrose was critical for increasing glycation. Even though some level of glycation was observed in lyophilized samples, the native structure of the protein was not affected. Further, it was demonstrated that storage of both lyophilized cakes and reconstituted formulations at higher temperatures could increase the extent of glycation in monoclonal antibody formulations., (Published by Elsevier B.V.)

Drug shortages and recalls are often caused due to particulate growth in parenteral products and can have serious clinical implications. Root cause analysis of such recalls and shortages may arise due to insufficient understanding of process, formulations issues and environmental effects than often reported filtration and inadequate personnel training. Therefore, the goal of this study was to use a model peptide hormone, secretin that is currently under drug shortage, and investigate the effect of excipients on the lyophilized secretin formulation and evaluate the effect of storage and excursion temperatures. Lyophilized formulation was assayed for secretin by reverse phase HPLC. Solid state characteristics of lyophilized formulation were determined by X-ray powder diffraction (XRPD), thermal and spectroscopic methods. Dynamic light scattering (DLS) was used to detect particulates in the formulation after reconstitution. To assess the environmental impact, the lyophilized samples were stored at -20°C, 4°C, 25°C and 25°C/60%RH and analyzed at time 0, 1, 4, and 8 weeks. HPLC analyses exhibited a decrease in secretin concentration by 8 week (20-27% fold decrease). Visual observation and DLS showed particulates and increased reconstitution time (e.g., at 25°C/60%RH, particle size of ∼390 nm at day 0 to >2 μm as early as week 1; reconstitution time of ∼20s at day 0 to ∼67s at week 8). XRPD, thermal and spectroscopic methods demonstrated polymorphic transitions of mannitol and increased crystallinity in the lyophilized formulations with time. These studies potentially address the effect of product excursions outside the proposed label storage conditions which is -20°C for secretin formulation and this is the first time it has been investigated. These observations indicate that both environmental factor and excipient may have an impact on the stability of secretin formulation and appearance of particles in the product., (Copyright © 2015. Published by Elsevier B.V.)

The objective was to quantify drug loss due to cold flow (CF) in marketed estradiol transdermal drug delivery systems (TDDS), and study its influence on the in vitro flux and drug transfer across contacting skin. TDDS samples (products-A and B) were induced with CF at 25 and 32°C/60% RH by applying 1-kg force for 72h. CF was measured as percent dimensional change and amount of drug loss/migration in CF region. In vitro drug permeation studies were conducted across human epidermis from TDDS excluding CF region, and CF region alone against control (without CF). In both products, significantly higher percentage of CF (dimensional change and drug migration) was observed at 32°C compared to 25°C. In vitro flux from both products excluding CF region either at 25 or 32°C was the same, but significantly lower compared to control. Drug transferred from CF region of product-A after 8h was the same at 25 and 32°C, but significantly higher in product-B. Flux from both products together with CF region at 32°C was significantly lower than that observed at 25°C. Results showed that excessive CF at storage (25°C) and clinical usage (32°C) conditions may have implications on product performance and safety of estradiol TDDS., (Published by Elsevier B.V.)

The purpose of this study is to assess the long-term stability of Prussian blue (PB) drug product (DP) and active pharmaceutical ingredient (API) under laboratory storage conditions by monitoring the loss in water content and the corresponding change of the in vitro thallium binding capacity that represents product performance. The bound water content and the in vitro thallium binding capacity of PB DPs and APIs were measured in 2003 and 2013, respectively. Water content, a critical quality attribute that directly correlates to the thallium (Tl) binding capacity was measured by thermal gravimetric analysis (TGA). The thallium binding study was conducted by testing PB in buffered solutions over the human gastrointestinal pH range with thallium concentrations ranging from 600 to 1,500 ppm. Samples were incubated at physiological temperature of 37°C in a shaking water bath to mimic gastric flux and intestinal transport. The binding equilibrium was reached at 24h. Following incubation, each sample was filtered and the free thallium was analyzed using a validated inductively coupled plasma spectroscopic method (ICP). The Langmuir isotherm was plotted to calculate maximum binding capacity (MBC). Compared with 2003, the water content of DP-1 decreased by about 14.1% (from 15.6 to 13.4 mol), and the MBC of DP-1 decreased by about 12.5% (from 714 to 625 mg/g) at pH 7.5. When low concentration of thallium (600 ppm) was used at pH 7.5, the Tl binding remained comparable for both API-1 (286 vs 276 mg/g) and DP-1 (286 vs 268 mg/g). Similarly, the Tl binding remained unchanged for both API-1 (237 vs 255 mg/g) and DP-1 (234 vs 236 mg/g) at pH 5.0. However, at pH 1.0 the binding was reduced 32.3% and 25.9% for API-1 and DP-1, respectively. Since the majority of binding takes place in the upper GI tract where pH around 5 can be expected, and therefore, the Tl binding capacity of PB should be comparable for new and aged samples. The findings that Tl binding changes with the water loss of PB and pH conditions are consistent with our previously published data. The study also represents the first quantitative assessment of the long-term stability of PB. Over last 10 years, PB DPs and APIs have lost about 20% water under ambient laboratory storage conditions which are consistent with a controlled warehouse environment. While the maximum binding capacity of PB to thallium was decreased after about 10 years of long-term storage, it is still very effective, suggesting that the shelf life of PB should be much longer than the manufacturer ascribed expiration date of 2008 under proper storage conditions., (Published by Elsevier B.V.)

Clinical performance of an amorphous solid dispersion (ASD) drug product is related to the amorphous drug content because of the greater bioavailability of this form of the drug than its crystalline form. Therefore, it is paramount to monitor the amorphous and the crystalline fractions in the ASD products. The objective of the present investigation was to study the feasibility of using a standardized X-ray powder diffraction (XRPD) in conjunction with chemometric methods to quantitate the amorphous and crystalline fraction of the drug in several tacrolimus ASD products. Three ASD products were prepared in which drug to excipients ratios ranged from 1:19 to 1:49. The amorphous and crystalline drug products were mixed in various proportions so that amorphous/crystalline tacrolimus in the samples vary from 0 to 100%. XRPD of the samples of the drug products were collected, and PLSR and PCR chemometric methods were applied to the data. The R(2) was greater than '0.987' for all the models and bias in the models were statistically insignificant (p>0.05). RMSEP and SEP values were smaller for PLSR models than PCR models. The models prediction capabilities were good and can predict as low as 10% when drug to excipient ratio is as high as 1:49. In summary, XRPD and chemometric provide powerful analytical tools to monitor the crystalline fractions of the drug in the ASD products., (Copyright © 2014. Published by Elsevier B.V.)

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted. The formulations were subjected to physicochemical characterization (drug particle size, spreadability, viscosity, pH, and drug concentration in aqueous phase) and in vitro drug release studies against RLD. The results demonstrated that DOE formulations were structurally and functionally (e.g., drug release) similar (Q3) to RLD. Moreover, in vitro drug permeation studies showed that extent of drug bioavailability/retention in human epidermis from F-12-F-14 were similar to RLD, although differed in rate of permeation. The results suggested generic acyclovir creams can be manufactured to obtain identical performance as that of RLD with Q1/Q2/Q3., (Published by Elsevier B.V.)

Particulate growth in parenteral product frequently results in product recalls causing drug shortages. While this is mostly attributed to quality issues in a firm, particulates growth could also be due to inadequate product, process, or environmental understanding. Therefore, the objective of this study was to use indomethacin sodium trihydrate (drug) as a model drug for lyophilization and evaluates short-term stability with respect to particulate growth at different storage temperatures. Under aseptic condition, each vial filled with filtered drug solution was lyophilized, and stoppered in LyoStar3. Crimped vials were kept at 5°C, 15°C, 25°C, 25°C/60%RH, and 40°C/75%RH. At predefined time interval, samples were characterized using X-ray powder diffraction (XRPD), thermal, and spectroscopic method. Lyophilized formulation showed four thermal events: 60-90°C demonstrating glass transition, 110-160°C showing recrystallization exotherm,170-220°C exhibiting endotherm of potential polymorph, and 250°C showing melting endotherm. XRPD of the lyophilized powder demonstrated peak at 2 θ 11.10. Spectroscopic studies of lyophilized powder indicated alteration in symmetric and asymmetric carboxylate peaks over time indicating initiation of crystallization and crystal growth. Reconstitution studies indicated higher reconstitution time after six weeks for sample stored at 40°C/75%RH. Furthermore, reconstituted solution showed presence of particulates after 8 weeks storage. These studies suggest that particulate growth can stem from poorly developed formulation and not necessarily due to frequently ascribed filtration issues., (Published by Elsevier B.V.)

The study objective was to evaluate the thermodynamic stability of iron sucrose complexes as determined by molecular weight (m.w.) changes. The first part of the study focused on the effect of thermal stress, pH, electrolyte or excipient dilution on the stability of a colloidal iron drug product. Part two focused on the physical and chemical evaluation of the colloidal nature of iron sucrose using a series of characterization experiments: ultracentrifugation, dialysis, particle size, zeta potential, and osmotic pressure analysis. A validated Taguchi-optimized high performance gel permeation chromatography method was used for m.w. determinations. Results indicate m.w. of the iron sucrose complex remained unchanged after excipient dilution, ultracentrifugation, dialysis, and electrolyte dilution. Electrolyte dilution studies indicated the lyophilic nature of the iron sucrose colloid with a particle size of 10nm and zeta potential of 0 mV. The complex deformed at low pH and reformed back at the formulation pH. The complex is stable under mild-to-moderate temperature <50°C but aggregates following prolonged exposure to high temperatures >70°C. In conclusion, the resistance of the complex to breakdown by electrolytic conditions, excipient dilution, ultracentrifugation and the reversible complexation after alteration of formulation pH suggest iron sucrose is a lyophilic colloid in nature and lyophilic colloidals are thermodynamically stable., (Published by Elsevier B.V.)

Background: Abnormalities of cyclic-AMP (cAMP) response element binding protein (CREB) function has been suggested in bipolar (BP) illness and schizophrenia (SZ), based on both indirect and direct evidence. To further elucidate the role of CREB in these disorders, we studied CREB expression and function in two brain areas implicated in these disorders, i.e., dorsolateral prefrontal cortex (DLPFC) and cingulate gyrus (CG)., Methods: We determined CREB protein expression using Western blot technique, CRE-DNA binding using gel shift assay, and mRNA expression using real-time RT-polymerase chain reaction (qPCR) in DLPFC and CG of the postmortem brain of BP (n=19), SZ (n=20), and normal control (NC, n=20) subjects., Results: We observed that CREB protein and mRNA expression and CRE-DNA binding activity were significantly decreased in the nuclear fraction of DLPFC and CG obtained from BP subjects compared with NC subjects. However, the protein and mRNA expression and CRE-DNA binding in SZ subjects was significantly decreased in CG, but not in DLPFC, compared with NC., Conclusion: These studies thus indicate region-specific abnormalities of CREB expression and function in both BP and SZ. They suggest that abnormalities of CREB in CG may be associated with both BP and SZ, but its abnormality in DLPFC is specific to BP illness., (© 2013 Published by Elsevier B.V.)

Crystallization of nimodipine in liquid-filled soft gelatin capsule during storage was reported for some commercial products, resulting in product recalls due to product quality and more importantly safety concerns. In this study, a real time particle monitoring tool, focused beam reflectance measurement, was used to evaluate the precipitation conditions of nimodipine in co-solvents. Upon water addition, two particle populations were discovered, appearing at different percentage of water content. Two transitions (i.e. sudden increase in particle counts) were observed, possibility related to nucleation and crystal growth of nimodipine. Furthermore, lowering storage temperature increased the tendency of nimodipine precipitation. Most critically, it was determined that with certain excipient, the drug precipitation occurred at approximately 7% (w/w) water content. Considering that all the orally administered liquid filled soft gelatin capsule shells contain residue water content as plasticizer, moisture transfer from the shell to the formulation may occur during long term storage, resulting in drug precipitation, particularly under cold temperature conditions., (Published by Elsevier B.V.)

The focus of present research was to understand and control the variability of solid dispersion (SD) formulation of non-ribosomal peptide antibiotic, vancomycin (VCM). Hunter screening design was constructed using seven independent variables namely melting temperature (X1), congealing temperature (X2), mixing time (X3), type of capsule shell (X4), filling method (X5), molecular weight of polyethylene glycol (PEG, X6) and surfactant type (X7), and responses measured were cumulative percentage of VCM released in 45 min (Y1) and potency (Y2). The SD formulations were prepared by melt-fusion method, and tested for dissolution, potency, and characterized by Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and near infrared chemical imaging (NIR-CI). Statistically significant (p<0.05) effect of congealing temperature (X2), type of capsule shell (X4), filling method (X5), molecular weight of PEG (X6) was revealed on Y1, and R(2) of 0.992 was obtained between experimental and predicted value. None of the factors have statistically significant (p>0.05) influence on Y2. SEM, DSC and PXRD indicated crystalline nature of SD formulations. Homogeneity of SD formulations was shown by NIR-CI images. In summary, the quality of VCM SD formulations could be assured by controlling the critical factors during manufacturing., (Published by Elsevier B.V.)

Nimodipine (NM) commercial formulation has been recalled due to drug crystallization in the product. Aim of present investigation was to systematically evaluate NM ternary cosolvents systems, characterize the crystallized drug and develop discriminating dissolution method that could detect the drug crystallization in the product. Mixture design was constructed using independent components namely water (X1), glycerin (X2) and polyethylene glycol 400 (X3, PEG-400). Nineteen formulations were developed using various level of cosolvents mixture while drug concentration was kept constant. The response selected was the drug crystallized in the formulations kept at four storage conditions 5 °C, 15 °C, 25 °C and 25 °C/60% RH for four weeks. The crystallized drug was characterized by Fourier transformed infrared (FTIR), near infrared (NIR), NIR-chemical imaging and Raman spectroscopies, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and scanning electron microscopy. Dissolution of formulation and modification was tested by USP method 2 in 0.25 and 0.50% sodium lauryl sulphate (SLS) aqueous media and run at 50 and 75 rpm. X1 promoted drug crystallization at all conditions of storage and reverse was true for X3. Characterization data indicated that the crystallized drug in most of the formulations were modification II, but a few formulations contained significant proportion of the modification I. Dissolution in 0.25% (w/v) SLS at 75 rpm was more discriminating in detecting the crystallization in the product compared to dissolution in 0.5% (w/v) SLS media. In summary, cosolvents system of NM was prone to crystallization depending upon the cosolvents composition and storage conditions. A more rational approach to develop NM formulation would entail a then through understanding of the causes of crystallization and their characterization in a variety of storage conditions., (Published by Elsevier B.V.)

An efficient and potentially scalable technology was evaluated to control the ice nucleation step of the freezing process for a model monoclonal antibody formulation and the effect on process performance and quality attributes of the final lyophilized product was compared with the conventional shelf ramping method of freezing. Controlled ice nucleation resulted in uniform nucleation at temperatures between -2.3 and -3.2 °C while uncontrolled nucleation resulted in random nucleation at temperatures between -10 and -16.4 °C. The sublimation rate (dm/dt) during primary drying was higher in the controlled nucleation cycle (0.13 g/h/vial) than in the uncontrolled nucleation cycle (0.11 g/h/vial). This was due to the formation of larger ice crystals, leading to lower product resistance (Rp) and 19% reduction in the primary drying for the controlled nucleation cycle. Controlled ice nucleation resulted in lyophilized cakes with more acceptable appearance, no visible collapse or shrinkage and decreased reconstitution times compared with uncontrolled nucleation. There were no observed differences in the particle size, concentration (A280 nm) and presence of aggregates (A410 nm) between the two nucleation cycles when the lyophilized cakes were reconstituted. These were confirmed by SEC and protein A-HPLC analyses which showed similar peak shapes and retention times between the two cycles. However, uncontrolled nucleation resulted in cakes with larger specific surface area (0.90 m(2)/g) than controlled nucleation (0.46 m(2)/g). SEM images of the lyophilized cakes from uncontrolled nucleation revealed a sponge-like morphology with smaller pores while cakes from controlled nucleation cycle revealed plate-like structures with more open and larger pores. While controlled nucleation resulted in a final product with a higher residual moisture content (2.1±0.08%) than uncontrolled nucleation (1.62±0.11%), this was resolved by increasing the secondary drying temperature., (Published by Elsevier B.V.)

The purpose of this study was to use QbD approaches to evaluate the effect of several variables and their interactions on quality of a challenging model murine IgG3κ monoclonal antibody (mAb), and then to obtain an optimized formulation with predefined quality target product profile. This antibody was chosen because it has a propensity to precipitate and thus represents a challenge condition for formulation development. Preliminary experiments were conducted to rule out incompatible buffer systems for the mAb product quality. A fractional factorial experimental design was then applied to screen the effects of buffer type, pH and excipients such as sucrose, sodium chloride (NaCl), lactic acid and Polysorbate 20 on glass transition temperature ( [Formula: see text] ), monoclonal antibody concentration (A(280)), presence of aggregation, unfolding transition temperature (T(m)) of the lyophilized product, and particle size of the reconstituted product. A Box-Behnken experimental design was subsequently applied to study the main, interaction, and quadratic effects of these variables on the responses. Pareto ranking analyses showed that the three most important factors affecting the selected responses for this particular antibody were pH, NaCl, and Polysorbate 20. The presence of curvature in the variables' effects on responses indicated interactions. Based on the constraints set on the responses, a design space was identified for this mAb and confirmed with experiments at three different levels of the variables within the design space. The model indicated a combination of high pH (8) and NaCl (50mM) levels, and a low Polysorbate 20 (0.008 mM) level at which an optimal formulation of the mAb could be achieved. Moisture contents and other analytical procedures such as size exclusion chromatography, protein A analysis and SDS-PAGE of the pre-lyophilized and final reconstituted lyophilized products indicated an intact protein structure with minimal aggregation after formulation and lyophilization. In conclusion, experimental design approach was effective in identifying optimal concentrations of excipients and pH for this challenging monoclonal antibody formulation., (Published by Elsevier B.V.)

The focus of present investigation was to evaluate the tannic acid (TA) complexes of cholorpheniramine maleate (CPM) and characterize it by a variety of physicochemical, dissolution, and electronic tongue methods. The complexes were prepared in various molar ratios by solvent evaporation method. They were characterized by spectroscopic, thermal, powder X-ray, electronic tongue, solubility and dissolution methods. FTIR (infrared red) spectra showed complex formation between the TA and CPM. Complex formation has significantly lowered the drug solubility and sustained its release for more than 24 h in phosphate buffer pH 6.8. On the contrary, the release was much faster in the presence of Avicel PH 113 in the same molar ratio complex. The complex formulation has suppressed the bitter taste of CPM as indicated by Euclidean distance in electronic tongue evaluation. NIR-CI (near infrared chemical imaging) showed lower skew value that indicated the homogenous distribution of formulation components. The chemometric models were also developed using the NIR data. The model based on second derivative data was better in predicting the TA and CPM loading as indicated by higher values of R, R(2) and lower values of root mean square error and standard errors. Furthermore, it has a better accuracy and less biased in comparison to other models. In conclusion, the CPM tannate has a sustained release behavior and excipients play a major role in modifying its release. Additionally, the complexes with varying molar ratio of tannate to CPM have differential taste masking abilities than that of the pure drug., (Published by Elsevier B.V.)

Quality by design (QbD) principles were explored in the current study to gain a comprehensive understanding of the preparation of superoxide dismutase (SOD) containing liposome formulations prepared using freeze-and-thaw unilamellar vesicles (FAT-ULV). Risk analysis and D-optimal statistical design were performed. Of all the variables investigated, lipid concentration, cholesterol mol%, main lipid type and protein concentration were identified as critical parameters affecting SOD encapsulation efficiency, while the main lipid type was the only factor influencing liposome particle size. Using a model generated by the D-optimal design, a series of three-dimensional response spaces for SOD liposome encapsulation efficiency were established. The maximum values observed in the response surfaces indirectly confirmed the existence of a specific SOD-lipid interaction, which took place in the lipid bilayer under the following optimal conditions: (1) appropriate membrane thickness and curvature (DPPC liposomes); and (2) optimal "pocket size" generated by cholesterol content. With respect to storage stability, the prepared SOD liposomes remained stable for at least 6 months in aqueous dispersion state at 4°C. This research highlights the level of understanding that can be accomplished through a well-designed study based on the philosophy of QbD., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A novel two-stage reverse dialysis method has been developed for in vitro release testing of liposomal drug product with passive targeting characteristics. The first stage of the test is to mimic the circulation of liposomes in the body, whereas the second stage is to imitate the drug release process at the target. Buffer and surfactant solution were used during the first and second stages, respectively. For formulations containing high phase transition temperature lipids and high cholesterol content, no drug leakage was observed during the first stage of test. In the second stage, however, formulations with different compositions showed significant differences in terms of drug release rate, and discriminatory ability of the method was demonstrated. On comparing two different membrane diffusion techniques, dialysis and reverse dialysis methods, the reverse dialysis method showed significantly lower variation, and therefore is the preferred method. The developed in vitro release testing method should help to distinguish formulations with varied compositions for quality control testing purposes. This two-stage reverse dialysis method may pave the way to the development of more bio-relevant release testing methods for liposomal drug products., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Different destructive and nondestructive analytical methods, namely powder X-ray diffractometry (PXRD), differential scanning calorimetry (DSC), Raman and near-infrared (NIR) spectroscopy and imaging, to detect and characterize tacrolimus trace crystallinity in an amorphous solid dispersion (SD) using chemometric analysis were developed. The SD was spiked with different percentages of the crystalline drug to construct an array of SDs with different crystallinity percentages. Partial least square (PLS) regression analysis was employed to compare the performance of the calibration models created using these analytical methods. The obtained results indicated a significant interaction between tacrolimus and the employed polymer and a drug dissolution dependency on the crystalline fraction within the SDs. Using two PLS factors, these analytical methods were ranked according to its specificity to detect the trace crystallinity of SDs as NIR>PXRD>Raman>DSC. Through the application of PLS, root-mean-squared error of calibration values of 2.91%, 5.36%, 7.07% and 11.58% were calculated for the calibration models constructed by NIR, PXRD, Raman and DSC, respectively. Having a prediction error of 2.1% and a correlation coefficient of 0.99, it is demonstrated that combined NIR imaging and chemometric analysis outperformed the other methods in detecting trace crystallinity in tacrolimus amorphous systems. The spatial distributions of amorphous and crystalline drug were also obtained in order to allow for studying the crystallization dissemination in the solid dispersions. Consequently, NIR and NIR imaging coupled with chemometry was shown to be a powerful tool for the prediction of drug crystallinity within SDs., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Two statistical designs were used in this case study as part of an investigation into the feasibility and the advantages of applying QbD concepts to liposome-based complex parenteral controlled release systems containing a hydrophilic active pharmaceutical ingredient (API). The anti-viral drug tenofovir was used as a model compound. First design (Plackett-Burman) was used to screen eight high-risk variables obtained from risk analysis and assess their impact on liposome characteristics (drug encapsulation efficiency, particle size, and physical stability). It was discovered that out of eight high-risk variables only lipid and drug concentration had significant effects on the drug encapsulation efficiency. This allowed the use of a central composite design (CCD) (with more predictive capability) to fully elucidate the relationship between lipid concentration, drug concentration and encapsulation efficiency. On comparing the CCD model generated response surface with additional data points, the accuracy and robustness of the model was confirmed. Using this developed model, the design space for tenofovir liposomes preparation has been established in a laboratory setting, within which the preparation variability is minimized. With regard to sample storage stability, it was shown that at 4°C the prepared tenofovir liposomes, dispersed in aqueous phase, achieved stability for at least 2 years. These principles can be applied to liposomes containing other hydrophilic APIs, and can provide time and cost saving to industrial formulation scientists, and result in a more robust liposome preparation process., (Copyright © 2011 Elsevier B.V. All rights reserved.)

A mathematical model has been developed to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes, and will be useful in formulation development to rapidly achieve optimized formulations. This model can also be used to compare drug encapsulation efficiencies of liposomes prepared via different methods, and will assist in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during liposome manufacturing for hydrophilic molecules. Liposome particle size as well as size distribution, lipid concentration, lipid molecular surface area, and bilayer thickness were used in constructing the model. Most notably, a Log-Normal probability function was utilized to account for sample particle size distribution. This is important to avoid significant estimation error. The model-generated predictions were validated using experimental results as well as literature data, and excellent correlations were obtained in both cases. A Langmuir balance study provided insight regarding the effect of media on the liposome drug encapsulation process. The results revealed an inverse correlation between media ionic strength and lipid average molecular area, which helps to explain the phenomenon of inverse correlation between media ionic strength and drug encapsulation efficiency. Finally, a web application has been written to facilitate use of the model allowing calculations to be easily performed. This model will be useful in formulation development to rapidly achieve optimized formulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this investigation was to evaluate the complexation potential of brompheniramine maleate (BPM) and tannic acid (TA) for sustained release and taste masking effects. The complexes (1:1-1:7 TA to BPM ratio) were prepared by the solvent evaporation method using methanol, phosphate buffer pH 6.8 or 0.1N HCl as common solvents. The complexes were characterized microscopically by scanning electron microscopy (SEM), chemically by Fourier transform infrared (FTIR) and solid-state NMR (SSNMR), thermally by differential scanning calorimetry (DSC), for crystallinity by powder X-ray powder diffraction (PXRD), for organoleptic evaluation by electronic tongue (e-tongue), and for solubility in 0.1N HCl and phosphate buffer pH 6.8. The dissolution studies were carried out using the USP II method at 50 rpm in 500 ml of dissolution media (0.1N HCl or phosphate buffer pH 6.8). SEM images revealed that the morphology of complexes were completely different from the individual components, and all complexes had the same morphological characteristics, irrespective of the solvent used for their preparation, pH or ratio of BPM and TA. The FTIR spectra showed the presence of chemical interactions between the TA and BPM. DSC, PXRD and SSNMR indicated that the drug lost its crystalline nature by formation of the complex. Complexation has significantly reduced the solubility of BPM and sustained the drug release up to 24h in phosphate buffer pH 6.8 media. The bitter taste of the BPM was completely masked which was indicated by Euclidean distance values which was far from the drug but near to its placebo in the complexes in all ratios studied. The taste masked complexes can be potentially developed as suitable dosage forms for pediatric use. In summary, complexation of BPM and TA effectively sustained the dissolution and masked the bitter taste of drug for the development of suitable dosage forms for pediatric use., (Published by Elsevier B.V.)

The purpose of this study was to extend QbD principles to liposomal drug products containing a hydrophilic active pharmaceutical ingredient (API) to demonstrate both the feasibility and the advantages of applying QbD concepts to liposome based complex parenteral controlled release systems. The anti-viral drug Tenofovir was selected as a model compound. Desired properties for two of the key liposome drug product qualities, namely the particle size and drug encapsulation efficiency, were defined and evaluated. It was observed that the liposome preparation process significantly affects liposome particle size, and this resulted in considerable variation in the drug encapsulation efficiency. Lipid chain length did not have a significant effect on drug encapsulation efficiency. However, lipid concentration did affect the drug encapsulation efficiency with higher lipid concentrations resulting in higher drug encapsulation. The use of risk assessment in this study assisted the identification of eight high risk factors that may impact liposome drug encapsulation efficiency and particle size., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The aim of this work was to develop an integrated process analytical technology (PAT) approach for a dynamic pharmaceutical co-precipitation process characterization and design space development. A dynamic co-precipitation process by gradually introducing water to the ternary system of naproxen-Eudragit L100-alcohol was monitored at real-time in situ via Lasentec FBRM and PVM. 3D map of count-time-chord length revealed three distinguishable process stages: incubation, transition, and steady-state. The effects of high risk process variables (slurry temperature, stirring rate, and water addition rate) on both derived co-precipitation process rates and final chord-length-distribution were evaluated systematically using a 3(3) full factorial design. Critical process variables were identified via ANOVA for both transition and steady state. General linear models (GLM) were then used for parameter estimation for each critical variable. Clear trends about effects of each critical variable during transition and steady state were found by GLM and were interpreted using fundamental process principles and Nyvlt's transfer model. Neural network models were able to link process variables with response variables at transition and steady state with R(2) of 0.88-0.98. PVM images evidenced nucleation and crystal growth. Contour plots illustrated design space via critical process variables' ranges. It demonstrated the utility of integrated PAT approach for QbD development., (Published by Elsevier B.V.)

The focus of present investigation was to assess the utility of non-destructive techniques in the evaluation of risperidone solid dispersions (SD) with methyl-β-cyclodextrin (MBCD) and subsequent incorporation of the SD into orally disintegrating tablets (ODT) for a faster release of risperidone. The SD was prepared by a solvent evaporation method and evaluated by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), near infrared spectroscopy (NIR), NIR-chemical imaging (NIR-CI), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). DSC and XRD analysis indicated that crystallinity of SD has reduced significantly. FTIR showed no interaction between risperidone and MBCD. Partial least square (PLS) was applied to the NIR data for the construction of chemometric models to determine both components of the SD. Good correlations were obtained for calibration and prediction as indicated by correlation coefficients >0.9965. The model was more accurate and less biased in predicting the MBCD than risperidone as indicated by its lower mean accuracy and mean bias values. SD-3 (risperidone:MBCD, 1:3) was incorporated into ODT tablets containing diluent (D-mannitol, FlowLac(®) 100 or galenIQ™-721) and superdisintegrant (Kollidon(®) CL-SF, Ac-Di-Sol or sodium starch glycolate). Disintegration time, T(50) and T(90) were decreased in the formulations containing mannitol and Kollidon(®) CL-SF, but increased with galenIQ™-721 and sodium starch glycolate, respectively. NIR-CI images confirmed the homogeneity of SD and ODT formulations., (Published by Elsevier B.V.)

The aim of this investigation was to screen and understand the product variability due to important factors affecting the characteristics CyA-PLGA nanoparticles prepared by O/W emulsification-solvent evaporation method. Independent variables studied were cyclosporine A (CyA) (X(1)), PLGA (X(2)), and emulsifier concentration namely SLS (X(3)), stirring rate (X(4)), type of organic solvent employed (chloroform or dichloromethane, X(5)) and organic to aqueous phase ratio (X(6)). The nanoparticles properties considered were encapsulation efficiency (Y(1)), mean particle size (Y(2)), zeta potential (Y(3)), burst effect (Y(4)) and dissolution efficiency (Y(5)). The statistical analysis of the results allowed determining the most influent factors. The nanoparticles were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The factors combination showed variability of entrapment efficiency (Y(1)), mean particle size (Y(2)) and zeta potential (Y(3)) from 10.17% to 93.01%, 41.60 to 372.80 nm and 29.60 to 34.90 mV, respectively. Initially, nanoparticles showed burst effect followed by sustained release during the 7-day in vitro release study period. The dissolution efficiency (Y(5)) varied from 52.67% to 84.11%. The nanoparticles revealed Higuchi release pattern and release occurred by coupling of diffusion and erosion. In conclusion, this study revealed the potential of QbD in understanding the effect of formulation and process variables on the characteristics on CyA-PLGA nanoparticles., (Copyright 2010. Published by Elsevier B.V.)

The stability of metoprolol tartrate tablets packaged in original high density polyethylene containers and repackaged in USP Class A unit-dose blister packs was investigated. Studies were conducted at 25 degrees C/60% relative humidity (RH) for 52 weeks and at 40 degrees C/75% RH for 13 weeks. The potency, dissolution, water content, loss on drying and hardness of the drug products were analyzed. Results indicated no differences in the stability between the tablets in both packages stored under 25 degrees C/60% RH. No difference in potency was found in both packages under either condition. However, a significant weight increase due to moisture uptake was observed for the repackaged tablets stored under 40 degrees C/75% RH. The weight increase was accompanied by a decrease in tablet hardness (6.5-0 kp) and a increase in dissolution rate (51-92%) in 5 min. Near-infrared (NIR) chemical imaging also monitored moisture uptake of the tablet non-invasively through the package. The observed changes in product stability may adversely affect the products bioavailability profile, even though the potency of the active drug remained within USP specification range of 90-110%. Study results suggest product quality can be negatively impacted even when using USP Class A repackaging materials., (Published by Elsevier B.V.)

The objective of this study was to develop an integrated multivariate approach to quantify the constituent concentrations of both drug and excipients of powder blends. A mixture design was created to include 26 powder formulations consisting of ibuprofen as the model drug and three excipients(HPMC, MCC, and Eudragit L100-55). The mixer was stopped at various time points to enable near infrared(NIR) scan of the powder mixture and sampling for UV assay. Partial least square (PLS), principal component regression (PCR), and multiple linear regression (MLR) models were established to link the formulation concentrations with the Savitzky-Golay 1st derivative NIR spectral data at various characteristic wavelengths of each component. PLS models based on the NIR data and UV data were calibrated and validated. They predicted the main components' concentrations well in the powder blends, although prediction errors were larger for minor components. As expected from the complete random-mixture (CRM) model, the measurement uncertainties were higher for minor components in the powder formulations. The prediction performance differences between the NIR model and UV model were explained in the context of scale of scrutiny and model applicability. The importance of understanding excipient variability in powder blending and its implication for blending homogeneity assessment is highlighted.

Ferric hexacyanoferrate, (Fe(4)(III)[Fe(II)(CN)(6)](3)), also known as insoluble Prussian blue (PB), is the active pharmaceutical ingredient (API) of Radiogardase which is the first approved drug product (DP) for treatment of thallium and radiocesium poisoning. The aim of this study is (1) to determine the in vitro thallium binding capacity and binding rates of insoluble PB; and (2) to evaluate the effect of physiological pH conditions, PB particle size and storage conditions on the binding to PB. Experimental pH levels from 1.0 to 7.5 were used to cover the range of pH levels that PB may encounter when traveling through the gastrointestinal (GI) tract in humans. Measurements of thallium binding were made between 1 and 24h, to cover gastric and intestinal tract residence time. PB was found to have a binding capacity of approximately 1400 mg/g at pH 7.5. When the pH decreased, the binding decreased as well. The results indicated that the hydration state of PB influences the thallium binding process. It was also found that there exits a direct correlation between the moisture loss in PB and the thallium binding rate constant. The PB with 17 mol of water had a binding rate constant of 0.52, which was reduced to 0.32 when PB was dehydrated to 2.5 mol of water. Significant differences were observed in both binding capacity and binding rate constant among PB fractions with different particle size ranges. PB fraction with particle size of 220-1000 microm had a binding rate constant of 0.43, which increased to 0.64 when the particle size was reduced to 32-90 microm. Batch-to-batch variation in thallium binding was also observed among the APIs and the DPs and this was related to particle size and hydration state. These findings can be utilized to evaluate and predict drug product quality under certain manufacturing and dry storage conditions.