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The aim of this paper was to investigate the effects of formulation parameters on the physicochemical and pharmacokinetic (PK) behavior of amorphous printlets of lopinavir (LPV) manufactured by selective laser sintering 3D printing method (SLS). The formulation variables investigated were disintegrants (magnesium aluminum silicate at 5-10%, microcrystalline cellulose at 10-20%) and the polymer (Kollicoat® IR at 42-57%), while keeping printing parameters constant. Differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared analysis confirmed the transformation of the crystalline drug into an amorphous form. A direct correlation was found between the disintegrant concentration and dissolution. The dissolved drug ranged from 71.1 ± 5.7% to 99.3 ± 2.7% within 120 min. A comparative PK study in rabbits showed significant differences in the rate and extent of absorption between printlets and compressed tablets. The values for T max , C max , and AUC were 4 times faster, and 2.5 and 1.7 times higher in the printlets compared to the compressed tablets, respectively. In conclusion, the SLS printing method can be used to create an amorphous delivery system through a single continuous process., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Many nitrosamines have been recognized to be carcinogenic for many decades. Despite the fact that several nitrosamine precursors are frequently used in the manufacturing of pharmaceutical products, their potential presence in pharmaceutical products has previously been overlooked due to a lack of understanding on how they form during the manufacturing process. From the risk assessment, it is clear that nitrosamines or their precursors may be present in any component of the finished dosage form. As a risk mitigation strategy, components with a high potential to form nitrosamine should be avoided. In the absence of suitable alternatives, sufficient measures to maintain nitrosamines below acceptable intake levels must be applied. Excipient manufacturing pathways must be extensively studied in order to identify probable excipient components that may contribute to nitrosamine formation. The manufacturers must not solely rely on pharmacopeial specifications for APIs and excipients, rather, they should also develop and implement additional strategies to control nitrosamine impurities. The formulation can be supplemented with nitrosating inhibitors, such as vitamin C, to stop the generation of nitrosamine. The purpose of this review is to identify key risk factors with regard to nitrosamine formation in pharmaceutical dosage forms and provide an effective control strategy to contain them below acceptable daily intake limits., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The focus of this research was to understand the effects of formulation and processing variables on the very-rapidly dissolving printlets of isoniazid (INH) manufactured by the selective laser sintering (SLS) three-dimensional (3D) printing method, and to characterize their physicochemical properties, stability, and pharmacokinetics. Fifteen printlet formulations were manufactured by varying the laser scanning speed (400-500 mm/s, X 1 ), surface temperature (100-110 °C, X 2 ), and croscarmellose sodium (CCS, %, X 3 ), and the responses measured were weight ( Y 1 ), hardness ( Y 2 ), disintegration time (DT, Y 3 ), and dissolution ( Y 4 ). Laser scanning was the most important processing factor affecting the responses. DT was very rapid (≥3 s), and dissolution (>99%) was completed within 3 min. The root-mean-square error in the studied responses was low and analysis of variance (ANOVA) was statistically significant ( p < 0.05). X-ray micro-computed tomography (micro-CT) images showed very porous structures with 24.6-34.4% porosity. X-ray powder diffraction and differential scanning calorimetry data indicated partial conversion of the crystalline drug into an amorphous form. The printlets were stable at 40 °C/75% RH with no significant changes in assay and dissolution. Pharmacokinetic profiles of the printlets and compressed tablets were superimposable. In conclusion, the rapidly dissolving printlets of the INH were stable, and oral bioavailability was similar to that of compositionally identical compressed tablets.

The focus of the present investigation was to develop amorphous glassy solutions (AGSs) of BCS Class II and IV drugs using sucrose acetate isobutyrate (SAIB). The drugs studied were rifaximin (RFX), dasatinib (DST), aripiprazole (APZ), dolutegravir (DLT), cyclosporine (CYS), itraconazole (ITZ), tacrolimus (TAC), sirolimus (SRL), aprepitant (APT), and carbamazepine (CBZ). AGSs were prepared by dissolving known quantity of the drug in the SAIB at 120 (TAC and APZ), 140 (CYS) or 150 o C (RFX, DST, DLT, ITZ, SRL, APT, and CBZ). They were characterized visually and by NIR, NIR hyperspectroscopy (NIR-H), and XRPD. Stability were determined by exposing open vials to 40 o C/75% RH for a week. AGSs behave like a glassy solid at room temperature and liquified above 60 o C. The solubility of APT, DLT, SRL, APZ, RFX, CBZ, TAC and CYS in SAIB was 0.4±0.0, 1.7±0.4, 1.9±0.0, 21.6±2.6, 36.4±0.9, 76.5±4.0, 115.1±2.3, and 239.0±12.6 mg/g, respectively. NIR, NIR-H, and XRPD data indicated the amorphous nature of the AGSs. Furthermore, AGSs were stable against devitrification on exposure to high temperature and humidity. In summary, SAIB can be employed to develop stable AGSs of poorly soluble drugs to increase dissolution, and oral bioavailability with the addition of hydrophilic excipients., (© 2021. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The objective of current research was to develop the models of dissolution prediction of tablets coated with cellulose acetate (CA 320S or CA 398-10) and cellulose acetate phthalate (C-A-P) blends. Independent variables selected were coating percent (X 1 ) and percent of CA 320S or CA 398-10 (X 2 ) in the blend. Dependent variables selected were dissolution in 1 (Y 1 ), 8 (Y 2 ), and 24 h (Y 3 ). Diclofenac sodium core tablets were coated with blend of either CA 320S and C-A-P or CA 398-10 and C-A-P at approximately 5, 7.5, and 10% weight gain. CA 320S and CA 398-10 content in the corresponding blends varied from 33.3-66.7% and 25.0-50.0% relative to C-A-P, respectively. Dissolution was performed in phosphate buffer 6.8 using USP apparatus 2. Coated tablets were also characterized for surface morphology and coating uniformity by near infrared hyperspectroscopy. Y 1 , Y 2 , and Y 3 were statistically (p < 0.05) affected by X 2 in CA 320S/C-A-P and CA 398-10/C-A-P blends coated tablets. On the other hand, X 1 had statistically significant (p < 0.05) effect only on the Y 3 in CA 320S/C-A-P while Y 1 was statistically (p < 0.05) affected by X 2 in CA 398-10/C-A-P. Analysis of variance also indicated statistically significant (p < 0.05) effect of the studied variables on the dependent variables for both the blends. The models were verified by independent experiment. Model predicted and empirical values of Y 1 , Y 2 , and Y 3 were close with maximum residual of 7.0%. In conclusion, dissolution can be modulated by varying composition of blend, polymer type, and coating weight.

Carbamazepine (CBZ) exists in anhydrous and dihydrate forms. These forms differ in their solubility, dissolution rate, and subsequently in their oral bioavailability. The objective of this study is to develop multivariate chemometric models for estimation of the low level of carbamazepine dihydrate (CBZ-DH) in the CBZ formulations containing excipients of the commercial formulation. The selected excipients were mixed in proportions to make sample matrices ranging from 0% to 50% CBZ-DH. Fourier transform infrared (FTIR), near infrared (NIR), and hyperspectral imaging data were mathematically pretreated before the development of partial least square and principal component analysis regression models. The developed partial least squares regression and principal component analysis models demonstrated predictability of CBZ and CBZ-DH by multiple scattering correction and standard normal variate processing methods. Among the spectroscopic techniques used the model performance parameters such as root-mean-square error, standard error, and bias were found to be low for NIR compared to FTIR. The treated data have shown better model fitting than without treatment, which was demonstrated by correlation coefficient of 0.9778, 0.9824, and 0.9852 for FTIR, NIR, and hyperspectral imaging, respectively. Furthermore, the predicted values were found to be very close to the selected low level of independent samples having 5% CBZ-DH in tablet formulation., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. 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.)

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 purpose of this research was to develop an orally disintegrating tablet (ODT) dosage form containing taste-masked beads of clindamycin HCl. Several formulation strategies were evaluated and a taste-masked ODT of clindamycin HCl was prepared without the use of a waxy cushioning agent. Clindamycin HCl (ca. 46% w/w) was coated onto microcrystalline cellulose beads (Cellets® 200) followed by the addition of a taste-masking layer of amino methacrylate copolymer, NF (Eudragit EPO® (EPO)) coating suspension. The efficiency of both the drug coating process and the taste-masking polymer coating process, as well as the taste masking ODTs was determined using potency and drug release analysis. Magnesium stearate was found to be advantageous over talc in improving the efficiency of the EPO coating suspension. A response surface methodology using a Box-Behnken design for the tablets revealed compression force and levels of both disintegrant and talc to be the main factors influencing the ODT properties. Blending of talc to the EPO-coated beads was found to be the most critical factor in ensuring that ODTs disintegrate within 30 s. The optimized ODTs formulation also showed negligible (<0.5%) drug release in 1 min using phosphate buffer, pH 6.8 (which is analogous to the residence time and pH in the oral cavity). By carefully adjusting the levels of coating polymers, the amounts of disintegrant and talc, as well as the compression force, robust ODTs can be obtained to improve pediatric and geriatric patient compliance for clindamycin oral dosage forms.

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 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.)

Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25 degrees C/60%RH), accelerated (40 degrees C/75%RH), and low-humidity (25 degrees C/0%RH and 40 degrees C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N(2)) and placed at 25 degrees C/0%RH and 40 degrees C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60 degrees C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.

Terahertz (THz) spectroscopy and chemometric analysis of resultant absorption spectra in the 30-500 cm(-1) range has been applied to perform quantitative determination of both active ingredient and excipient concentrations of tablets. Tests were performed on a series of tablets composed of various concentrations and processes of theophylline formulated with lactose, magnesium stearate, starch or Avicel, and as a function of tablet hardness. Transmission spectra of polyethylene pellets derived from each of the samples were analyzed using three approaches. Spectral superposition method was used as an indirect measure to examine whether and when the interaction among various pharmaceutical components and the tableting history could be considered insignificant for quantification purpose. Spectral characteristic peak method was able to correlate peak maxima with correction for tablets having the same hardness. Multivariate analysis (PCR and PLS 1) was capable of correlating THz spectra with tablet concentrations. The predicted concentrations of independent samples using multivariate models agreed well with nominal concentrations. The best correlations were obtained using multivariate analysis. With these studies, the advantage of using multivariate approach was demonstrated for process analytical technology (PAT) application. Further, the feasibility of integrating THz spectroscopy and chemometrics for the purpose of quantifying pharmaceutical tablet concentrations was demonstrated.

The usefulness of enzyme inhibitors and absorption enhancers with least mucosal cell cytotoxicity was evaluated on Caco-2 cell monolayers. The temporal cytotoxicity of several protease inhibitors at 500 microg/mL (e.g., turkey and chicken ovomucoids, aprotinin, and Protease Inhibitor Cocktail) and absorption enhancers [e.g., cholate (3%), glycocholate (3%), glycosursodeoxycholate (3%), ethylenediaminetetraacetic acid (EDTA, 0.1%), hydroxypropyl-beta-cyclodextrin (HP-beta-CD, 5%), hydroxypropyl-gamma-cylcodextrin (HP-gamma-CD, 5%), gamma-cylcodextrin (gamma-CD, 5%), tetradecyl-beta-D-maltoside (0.25%), octylglucoside (0.25%), citric acid (10%), glycyrrhetinic acid (0.34 mM), and Tween-80 (0.1%)] was measured by monitoring their effect on Caco-2 cell viability. Cell viability was measured by mannitol permeability measurements, transepithelial electrical resistance (TEER) measurements, DNA-propidium iodide staining assay, and WST-1 assay (tetrazolium salt based assay). Sodium dodecyl sulfate (0.1%), a potent surfactant, was used as a positive control. Chicken and turkey ovomucoids were nontoxic to cells as evaluated by all the methods used. Aprotinin decreased the TEER, whereas plasma membrane damage was seen with Protease Inhibitor Cocktail after a 24-h period. With respect to the absorption enhancers, the toxicity increased directly as a result of an increase in the time of incubation. The enhancers EDTA and HP-beta-CD can be used safely for a short period of time, whereas glycosursodeoxycholate, glycyrrhetinic acid, octylglucoside, HP-gamma-CD, and gamma-CD can be used for a longer period., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association.)

This study is the second in a series that examines the characterizing and selection of suitable grades of lactose for capsule formulation development. Based upon the previous study, four grades were selected for further study. The effects of drug load and operational variables on formulations derived from these four lactose types were evaluated for physicochemical and mechanical attributes of plugs and their capsules on an instrumented dosing-disc capsule filling machine (H&H KFM/3) using acetaminophen as a model, highly soluble and poorly compressible drug. The results obtained were as follows: (1) flowability reduced upon increasing drug load; (2) powder bed height (PBH) and compression force (CF) had positive significant effect on plug weight (p < 0.05); (3) ejection force was positively and significantly correlated with increasing speed and CF (p < 0.05); (4) AL capsule plugs had the highest plug crushing force which was followed by DCL15; (5) the crushing strength of plugs made from DCL11 increased with increasing acetaminophen concentration; (6) higher CF had a significant negative impact on acetaminophen release at 15 min time point (p < 0.05); (7) at 10% and 40% drug load, formulations containing AL showed the quickest drug release; and (8) increased drug load had a significant negative impact on the release rate at 15 and 45 min time points (p < 0.05). Overall, the results from this study provides information on risk based assessment of filler selection based on drug load and the range of machine operating variables which will help in defining criteria for meeting key quality attributes for capsule formulation development. [ABSTRACT FROM PUBLISHER]

A case study has been developed to illustrate one way of incorporating a Quality by Design approach into formulation and process development for a small molecule, freeze-dried parenteral product. Sodium ethacrynate was chosen as the model compound. Principal degradation products of sodium ethacrynate result from hydrolysis of the unsaturated ketone in aqueous solution, and dimer formation from a Diels-Alder condensation in the freeze-dried solid state. When the drug crystallizes in a frozen solution, the eutectic melting temperature is above −5°C. Crystallization in the frozen system is affected by pH in the range of pH 6-8 and buffer concentration in the range of 5-50 mM, where higher pH and lower buffer concentration favor crystallization. Physical state of the drug is critical to solid state stability, given the relative instability of amorphous drug. Stability was shown to vary considerably over the ranges of pH and buffer concentration examined, and vial-to-vial variability in degree of crystallinity is a potential concern. The formulation design space was constructed in terms of pH and drug concentration, and assuming a constant 5 mM concentration of buffer. The process design space is constructed to take into account limitations on the process imposed by the product and by equipment capability. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop an integrated process monitoring approach for evaluating powder blending process kinetics and determining blending process end-point. 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 spectroscopy scan of the powder mixture for obtaining the time course of the blending process. The evaluation of the blending process kinetics and process end-point was studied through three quantitative approaches: (1) Spectra linear superposition method; (2) Characteristic peak method; (3) Moving block standard deviation method. It was found that the powder blending experienced an initial rapid process to reach a quasi- end point within the first few minutes. Afterwards, a demixing occurred. Then, a real blending end-point was reached as characterized by an inflection point. ANOVA shows that the compositions of ibuprofen and MCC are the most statistically significant variables that impact the time required to reach the blending end-point. This highlighted the critical importance of developing quantitative chemometric approaches to extract critical process information and generate essential process knowledge to enable real-time release of the blending process. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2784–2798, 2009 [ABSTRACT FROM AUTHOR]

Abstract: 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 0mV. 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 2 θ 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Warfarin sodium ( WS) exists in multiple solid-state forms. The solid-state forms differ in physicochemical properties, and crystalline changes in the drug formulation may influence on the drug product quality and/or clinical performance. It is, therefore, critically important to have a good and reliable analytical method to monitor and quantitate this transformation during stability studies. The aim of the present research was to investigate Raman spectroscopy and solid-state nuclear magnetic resonance (13 C ss NMR) methods in conjunction with chemometry to quantitate the amorphous and crystalline WS fractions in the drug products. Compositionally identical formulations of amorphous and crystalline WS were prepared, and mixed in various proportions to make 0%-100% amorphous/crystalline sample matrices. Raman and 13 C ss NMR spectra were collected and subjected to partial-least-squares and principle component regressions after mathematical treatment of the data. The model performance parameters such as root-mean-square error of prediction, standard error of prediction, and bias were low for Raman models in comparison to 13 C ss NMR models. Models predicted values of the independent sample matrices match closely with the actual values at high level of crystalline WS. Thus, the developed methods provide means to control and quantitate the WS forms fraction in the drug product. Published 2015. This article is a U.S. Government work and is in the public domain in the USA 104:2550-2558, 2015 [ABSTRACT FROM AUTHOR]

The objective of this study was to develop a level A in vitro–in vivo correlation ( IVIVC ) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6 mg (delivery rates of 25, 50 and 100 μg/day, respectively) was deconvoluted using Wagner–Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R 2 = 1.0) with a polynomial regression of Y = − 0.227X 2 + 0.331X − 0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100 μg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for C max and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100 μg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100 μg/day. [ABSTRACT FROM AUTHOR]

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 (1 mg/ml and 20 mg/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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The objective of this study was to develop powder X-ray diffraction ( XRPD) chemometric model for quantifying crystalline tacrolimus from solid dispersion ( SD). Three SDs (amorphous tacrolimus component) with varying drug to excipient ratios (24.4%, 6.7%, and 4.3% drug) were prepared. Placebo SDs were mixed with crystalline tacrolimus to make their composition equivalent to three SD (crystalline tacrolimus component). These two components were mixed to cover 0%-100% of crystalline drug. Uniformity of the sample mixtures was confirmed by near-infrared chemical imaging. XRPD showed three distinct peaks of crystalline drug at 8.5°, 10.3°, and 11.2° (2 θ), which were nonoverlapping with the excipients. Principal component regressions ( PCR) and partial least square (PLS) regression used in model development showed high R2 (>0.99) for all the mixtures. Overall, the model showed low root mean square of standard error, standard error, and bias, which was smaller in PLS than PCR-based model. Furthermore, the model performance was evaluated on the formulations with known percentage of crystalline drug. Model-calculated crystalline drug percentage values were close to actual value. Therefore, these studies strongly suggest the application of chemometric- XRPD models as a quality control tool to quantitatively predict the crystalline drug in the formulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2819-2828, 2014 [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]