Excipient Components Research Articles

REVIEW: ANTIBACTERIAL, ANTIFUNGAL AND WOUND HEALING ACTIVITY OF NANOEMULGEL FORMULATIONS AND PHYSICAL CHARACTERISTICS

Nanoemulgel is an emulsion preparation with a droplet size of 1–100 nm suspended in a hydrogel. This review delves into the research on the impact of incorporating excipient components in nanoemulgel formulations to create products with specific physical attributes for different active ingredients with antifungal, antibacterial, and wound-healing properties. The research approach involves comparing articles on nanoemulgel preparation formulations with different combinations of active ingredients and excipients, as well as their pharmacological effects. Enhancing the level of active ingredients and altering the excipients can boost the effectiveness of nanoemulgel formulations in combating fungi, bacteria, and promoting wound healing. The review includes articles published within the past decade. Keywords: Nanoemulgel, Pharmacological activity, Physical characteristics, Review

Development and characterization of self-micro emulsifying drug delivery system of cilnidipine using simplex centroid mixture design

Objective: The main objective of the current research work was development and characterization of self-micro emulsifying drug delivery system of cilnidipine which is poorly water soluble drug. The improved solubility could offer improved dissolution as well as oral bioavailability. Method: Component excipients were selected based on the preliminary studies, capryol 90 and triacetin (1:1) selected as an oil, tween 80 selected as surfactant, transcutol p selected as co-surfactant based on the maximum solubility and better emulsification efficiency. The ternary phase diagram was constructed to identify the optimum composition of the formulation. Simplex centroid mixture design was applied for selection of optimized batch of SMEDDS. Capryol 90 and triacetin, tween 80 and transcutol p were taken as an independent variables X1, X2 & X3 respectively, while emulsification time (Y1) and % drug release at 2 minute (Y2) were taken as dependent variables. Optimized SMEDDS was evaluated based on % transmittance, emulsification time, globule size, PDI, % drug release, and cloud point. After that, SMEDDS were filled in capsule and short term stability study was done and SMEDDS compared with pure drug for dissolution profile. Result and discussion: Optimized batch containing capryol 90 and triacetin (1:1), tween 80 and transcutol p at a concentration of 10%, 67% and 23% respectively. The solubility of cilnidipine is increased by using capryol 90 and triacetin (1:1) as an oily phase. All the evaluation parameters of the optimized SMEDDS were met the acceptance criteria. Optimized batch of SMEDDS showed > 90% drug release within 2 minutes. Dissolution was improved as compared to the pure drug. Conclusion: A self-micro emulsifying drug delivery system of cilnidipine was developed successfully. Present work demonstrated for improving the dissolution of cilnidipine. This may lead to improved oral bioavailability of cilnidipine for the treatment of hypertension.

Identification and Separation of the Degradation Products of Vildagliptin Tablets and Raw Material using LC-MS and NMR, and then Exploration of the Corresponding Degradation Pathways

A gradient high performance liquid chromatography (HPLC) method has been developed for the qualitative and quantitative analyses of vildagliptin related substances. This method is based on using of RP-C18 (250 × 4.6 mm×5µm) and gradient elution with phosphate buffer and methanol as mobile phase. Various forced degradation studies were conducted to establish an impurity profile for vildagliptin in the tablet formula. Three degradation products were produced upon exposing vildagliptin to different degradation conditions (acidic, basic, oxidative, photolytic, aqueous and thermal); their structures were characterized using LC-MS and NMR (1H NMR, 13C NMR and DEPT) techniques. Some excipient components, examined in this study, had major effect towards producing any extra new degradation products.

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

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

Overview on Functionality Added Co-processed Excipients for Orodispersible Tablets

Orally disintegrating tablets are an emerging trend in novel drug delivery system and have received ever increasing demand during the last few decades. Orally disintegrating tablets ODTs are the dosage form which will disintegrate in mouth within seconds without need of water. This type of property in dosage form can be attained by addition of different varieties of excipients. But the number of fillers/binders/disintegrant which can be used for ODT formulations is limited because these bulk excipients have to fulfill special requirements, such as being soluble in water, pleasant taste, mouth feel, sweetness, and rapid dispersibility. In recent years drug formulation scientists have recognized that single component excipients do not always provide the requisite performance to allow certain active pharmaceutical ingredients to be formulated or manufactured adequately. New combinations of existing excipients are an interesting option for improving excipient functionality now a day. In excipients mannitol is used as diluents but now a day’s modified mannitol is available which give extensive flow, compression and rapid dispersibility to the tablet e.g. like Orocell, Mannogem EZ, and Pearlitol SD 200. The current review article is prepared to have a look over the recent development in excipient technology and the approaches involved in development of such excipients. It emphasizes on the different examples of functionality added materialsalso called as multifunctional co processed excipients available in market such as Ludiflash, Pharmburst, and F- MELT.

A Review on Multifunctional Excipients with Regulatory Considerations

The practice of multifunctional excipients is gaining more and more attention as it simplifies the process of drug formulation by substituting the necessity of using mixture of many excipients. The multifunctional excipients are the class of excipients which includes pre-–processed and co-processed excipients and it provides added functionalities to the formulation. Functionality of an excipient is a useful property which helps in manufacturing and improves quality as well as applicability of the material. Researchers have identified that single component excipients may not always give the required results during development and manufacturing of definite API, hence they are concentrating to develop multifunctional excipients which will have improved quality that will fulfil the requirements of the formulation experts in terms of cost. The cost of new excipient development is very high as it demands toxicity studies, hence the industry is now focusing on co-processing of approved materials. The demand for directly compressible co-processed excipients has also increased due to the availability of high-speed tableting machines, time saving in Abbreviated New Drug Application (ANDA), simplified validation and stability of active ingredients. The intention of this review article is to highlight applicability and increasing attention focusing the benefits of co-processed excipients. Their advantages over conventional blend of excipients include development methods, testing and also highlighting their regulatory consideration.

Formulation and Evaluation of α-Pinene Loaded Self-emulsifying Nanoformulation for In-Vivo Anti-Parkinson's Activity.

The present study was aimed to developed and optimize the self-nano emulsifying drug delivery system of α-pinene (ALP-SNEDDS) and evaluate its in-vivo anti-Parkinson's activity. Different lipid-based drug delivery technologies have been researched to upgrade drug bioavailability and expand their clinical adequacy upon oral administration. Self-emulsifying drug delivery systems (SEDDS) have pulled in developing the interest specifically for self nano emulsifying drug delivery systems (SNEDDS). The present work was attempted to improve the bioavailability of the ALP by defining the role of self-nano emulsifying formulations for its neuroprotective effect. Miscibility of the ALP was estimated in various excipient components to select the optimized combination. Self-nano emulsification, thermodynamic stability, the effect of dilution on robustness, optical clarity, viscosity, and conductivity tests were performed. The in-vivo anti-Parkinson's activity of the ALP-SNEDDS formulations were done using Pilocarpine antagonism induced Parkinsonism in rodents. Behavioral tests like tremulous jaw movements, body temperature, salivation, and lacrimation are performed. Two optimized formulations, composed of Anise oil, Tween 80, and Transcutol-HP of Oil: Smix ratio (4:6 and 3:7) were selected. The Smix ratio for both the formulation was 2:1. The particle size was found to consistent with the increase in dilution. The mean negative zeta potential of the formulations was found to be increased with an increase in dilution. The TEM images of the formulations revealed spherical shape of the droplet. The in-vitro drug release profile was found to be significant as compared to plain ALP suspension. The results of in-vivo studies indicate that nanosizing and enhanced solubilization of oral ALP-SNEDDS formulations significantly improved the behavioral activities compared to plain ALP suspension.

Effect of whole green tea products including catechins, polysaccharides, and flavonols on the metabolism of added sugars

The current study was investigated the effect of catechin rich green tea extracts (GTE) formulated with excipient components, crude tea polysaccharides (CTP), and flavonols (FVN) derived from green tea on sucrose hydrolysis and intestinal transport of monosaccharides using an in vitro digestion system with Caco-2 cell. Sucrose (10 mg) co-digested with GTE (1 mg) + FVN (0.01 mg) or GTE (1 mg) + CTP (0.1 mg) + FVN (0.01 mg) was less hydrolyzed into glucose and fructose, which showed 90.4 ± 1.36% and 91.75 ± 1.48% for the control (sucrose), respectively. Approximately 65.59% of the glucose released from the sucrose digested with GTE (1 mg) + CTP (0.1 mg) + FVN (0.01 mg) was subsequently transported by Caco-2 cell, which was significantly lower than other treatments (p < 0.05). The intestinal transport of fructose was inhibited by the co-digestion with GTE (1 mg) + FVN (0.01 mg) (43.65% of control) and GTE (1 mg) + CTP (0.1 mg) + FVN (0.01 mg) (43.12% of control). When glucose or fructose was directly treated to Caco-2 cell, glucose transport was inhibited in GTE (60.7% of control), while fructose transport was repressed in GTE + CTP + FVN (54.75% of control). Epithelial permeability (%) of the glucose and fructose ranged from 14.77 to 24.33% and 1.5–2.24%, respectively. Results suggest that co-intake catechin rich extract of catechin rich extract with polysaccharides and flavonols derived from green tea processing could be potential hypoglycemic ingredients when added sugars are consumed.

Toward simplified oral lipid-based drug delivery using mono-/di-glycerides as single component excipients

Objective This study aimed to systematically explore compositional effects for a series of lipid systems, on the in vitro drug solubilization and in vivo bioavailability of three poorly water-soluble drugs with different physico-chemical properties. Significance While many lipid-based drug products have successfully reached the market, there is still a level of uncertainty on the design guidelines for such drug products with limited understanding on the influence of composition on in vitro and in vivo performance. Methods and Results Lipid-based drug delivery systems were prepared using either single excipient systems based on partially digested triglycerides (i.e. mono- and/or di-glycerides) or increasingly complex systems by incorporating surfactants and/or triglycerides. These lipid systems were evaluated for both in vitro and in vivo behavior. Results indicated that simple single component long chain lipid systems are more beneficial for the absorption of the weak acid celecoxib and the weak base cinnarizine compared to equivalent single component medium chain lipid systems. Similarly, a two-component system produced by incorporating small amount of hydrophilic surfactant yields similar overall pharmacokinetic effects. The lipid drug delivery systems based on medium chain lipid excipients improved the in vivo exposure of the neutral drug JNJ-2A. The higher in vivo bioavailability of long chain lipid systems compared to medium chain lipid systems was in agreement with in vitro dilution and dispersion studies for celecoxib and cinnarizine. Conclusions The present study demonstrated the benefits of using mono-/di-glycerides as single component excipients in LBDDS to streamline formulation screening and improve oral bioavailability for the three tested poorly water-soluble drugs.

Morphological evaluation of low-dose midazolam granules by laser Raman microscopy.

Raman analysis has higher sensitivity for the detection of active pharmaceutical ingredients (APIs) than additives; thus, it is expected to be used for the evaluation of low-content preparations. The purpose of this study was to clarify the usefulness of granule morphology assessment using Raman analysis in the development of low-content formulations. In this study, midazolam was used as a model drug to prepare granules as a low-content formulation. Raman images were used to visualize the distribution of ingredients on the surface of the granules, determine the particle size of midazolam bound to the granules, and investigate the types of excipient components to which midazolam is bound. It was suggested that midazolam particles of a certain size were difficult to bind to excipients and had particularly low adhesion to mannitol. It was revealed that this phenomenon caused the segregation of the content of midazolam particles in the granules. Therefore, to obtain granules with good content uniformity, it was considered necessary to control the particle size of the API and select an additive that does not differ in adhesiveness to the main drug. Additionally, the findings obtained by morphological observation could be clarified by the quantitative evaluation of additives using Raman.

Assessment of the Higher‐Order Structure of Formulated Monoclonal Antibody Therapeutics by 2D Methyl Correlated NMR and Principal Component Analysis

Characterization of the higher-order structure (HOS) of protein therapeutics, and in particular of monoclonal antibodies, by 2D 1 H-13 C methyl correlated NMR has been demonstrated as precise and robust. Such characterization can be greatly enhanced when collections of spectra are analyzed using multivariate approaches such as principal component analysis (PCA), allowing for the detection and identification of small structural differences in drug substance that may otherwise fall below the limit of detection of conventional spectral analysis. A major limitation to this approach is the presence of aliphatic signals from formulation or excipient components, which result in spectral interference with the protein signal of interest; however, the recently described Selective Excipient Reduction and Removal (SIERRA) filter greatly reduces this issue. Here we will outline how basic 2D 1 H-13 C methyl-correlated NMR may be combined with the SIERRA approach to collect 'clean' NMR spectra of formulated monoclonal antibody therapeutics (i.e., drug substance spectra free of interfering component signals), and how series of such spectra may be used for HOS characterization by direct PCA of the series spectral matrix. © 2020 U.S. Government. Basic Protocol 1: NMR data acquisition Basic Protocol 2: Full spectral matrix data processing and analysis Support Protocol: Data visualization and cluster analysis.

Functionality evaluation of co-processed excipients as diluents in tablets manufactured by wet granulation

Abstract Diluents are essential components of a tablet formulation. The type of diluent used in a formulation influences the quality of tablets produced from that formulation. The aim of this study was to evaluate the tableting properties of co-processed excipients (C-PEs) incorporated as diluents in tablet formulation by wet granulation. Metronidazole tablets were prepared by wet granulation incorporating different diluents that were either single component excipients (SCEs) (lactose and microcrystalline cellulose) or C-PEs (Ludipress®, StarLac®, Prosolv® and AVICEL®HFE). The granules obtained for each formulation were evaluated for particle size analysis, flow properties and compression properties. Tablets weighing 500 mg were compressed from the metronidazole granules on a Single Station Tablet Press using a 12 mm punch and die tooling system. The tablets were kept for 24 h post-production, and the properties of weight uniformity, thickness, tensile strength, friability, disintegration time and dissolution profile evaluated subsequently. Results of granule properties showed that variations in parameters evaluated was as a result of differences in the type and composition of diluent used in formulation. Compactibility and tabletability profile of metronidazole granules revealed a better performance with granules processed with C-PE based diluents compared to SCE-based diluents. Tablets formulated with C-PEs as diluents were uniform in tablet weight, disintegrated faster and yielded a faster drug release compared to tablet formulations containing SCEs as diluent. This study reveals the performance advantage of C-PEs as diluents in tablets manufactured by wet granulation and highlights the importance of rational selection of excipients during tablet formulation.

Thermophysical Fingerprinting of Probiotic-Based Products

Variability in efficacy and safety is a worldwide concern with commercial probiotics for their growing and inevitable use in food and health sectors. Here, we introduce a probiotic thermophysical fingerprinting methodology using a coupling thermogravimetry and differential scanning calorimetry. Qualitative and quantitative information on the material decomposition and transition phases is provided under heating conditions. By monitoring the changes in both mass and internal energy over temperature and time, a couple of thermal data at the maximum decomposition steps allow the creation of a unique and global product identity, depending on both strain and excipient components. We demonstrate that each powder formulation of monostrain and multistrain from different lots and origins have a unique thermophysical profile. Our approach also provides information on the formulation thermostability and additive/excipient composition. An original fingerprint form is proposed by converting the generated thermal data sequence into a star-like pattern for a perspective library construction.

Quantifying Disproportionation in Pharmaceutical Formulations with 35Cl Solid-State NMR.

Reliable methods for the characterization of drug substances are critical for evaluating stability and bioavailability, especially in dosage formulations under varying storage conditions and usage. Such methods must also give information on the molecular identities and structures of drug substances and any potential byproducts of the formulation process, as well as providing a means of quantifying the relative amounts of these substances. For example, active pharmaceutical ingredients (APIs) are often formulated as ionic salts to improve the pharmaceutical properties of dosage forms; however, exposure of such formulations to elevated temperature and/or humidity can trigger the conversion of an ionic salt of an API to a neutral form with different properties, through a process known as disproportionation. It is particularly challenging to identify changes of pharmaceutical components in solid dosage formulations, which are complex heterogeneous mixtures of the API and excipient components (e.g., binders, disintegrants, and lubricants). In this study, we illustrate that ultra-wideline (UW) 35Cl solid-state NMR (SSNMR) can be used to characterize the disproportionation reaction of pioglitazone HCl (PiogHCl) in mixtures with metallic stearate excipients. 35Cl SSNMR can quantitatively detect the amount of PiogHCl in mixed samples within ±1 wt % and measure the degree of PiogHCl disproportionation in formulation samples stressed at high relative humidity and temperature. Unlike other methods used for characterizing disproportionation, our experiments directly probe the Cl- anions in both the intact salt and disproportionation products, revealing all of the chlorine-containing products in the solid-state chemical reaction without interfering signals from the formulation excipients.

Co Processed Excipients for Tabletting: Review Article

This main aim of the current review article is to provide a complete overview on recent development in excipient technology and the approaches involved in development of such excipients. Formulation scientists recognized that single component excipients do not always provide the requisite performance to allow certain active pharmaceutical ingredients to be formulated or manufactured adequately and they have focused their attention on the production of multifunctional excipients with enhanced performance to meet the needs of formulation experts in terms of costs of production, enhanced excipient functionality and quality of tablets. Manipulation in the functionality of excipient is provided by the co-processing of two or more existing excipients. Tablet manufacturing has been changed by the introduction of the direct-compression process and high-speed machines. These two developments have increased the demands on the functionality of excipients in terms of flow and compression properties. Direct compression is the preferred method for the preparation of tablets. The shift in tabletting toward direct-compression and high-speed manufacturing has forced the excipient industry to search for new excipients. The excipient industry, which has largely been an extension of the food industry, has taken up the novel use of particle engineering and material sciences to pave the way for a new category of functional excipients called co processed excipients. The coprocessing is the most widely explored method for the preparation of directly compressible adjuvants because it is cost effective and can be prepared in-house based on the functionality required.

Development and Characterization of Multifunctional Directly Compressible Co-processed Excipient by Spray Drying Method.

The present investigation was carried out to develop and characterize a multifunctional co-processed excipient for improving the compressibility of poorly compressible drugs. Etodolac was used as a model drug. Microcrystalline cellulose (MCC), lactose monohydrate (lactose), and StarCap 1500 (StarCap) were selected as components of the co-processed excipient. The spray drying method was used for co-processing of excipients. D-optimal mixture design was applied to optimize the proportion of component excipients. Statistical analysis of the D-optimal mixture design revealed that all response variables were significantly affected by the independent variables (p value < 0.05). Optimized composition was obtained from the desirability function. The optimized composition of the co-processed excipient was found to be 30% MCC, 25% lactose, and 45% StarCap. This optimized batch was evaluated for flow properties, compressibility parameters such as Kawakita's and Kuno's equation and Heckel's equation, and dilution potential. Evaluation parameters for flow properties (angle of repose, Carr's index, and Hausner's ratio) suggested excellent flow character. The parameters of Kawakita's and Kuno's equation and Heckel's equation suggested improvement in the compressibility of the model drug. Dilution potential was found to be 40%, and based on that, tablets of the model drug were formulated and evaluated for general evaluation parameters of tablets. All the parameters were found to be within the acceptance criteria which concluded that the multifunctional directly compressible co-processed excipient was prepared successfully that improved the compressibility of the poorly compressible model drug etodolac along with spray drying as an efficient method for the preparation of co-processed excipient.

Formulation factors affecting the isomerization rate of betamethasone-17-valerate in a developmental hydrophilic cream – a HPLC and microscopy based stability study

The formulation of betamethasone-17-valerate (BV) into topical medicines presents a significant challenge for the formulation chemist. The substance is susceptible to acid and base catalyzed isomerization in aqueous environments, which results in valerate transesterification from carbon 17 to carbon 21 of the steroid ring system. This acyl migration process is of significant clinical importance since the 21-valerate ester possesses only a fraction of the potency of the 17-valerate parent compound. Isomerization of BV should therefore be reduced to a minimum through design of a suitable drug vehicle. In this study, the effect of varying the concentration of several excipient components on the isomerization rate of betamethasone valerate in a model hydrophilic cream has been investigated. These excipients include the emulsifier macrogolstearylether-20/21, the co-emulsifier cetylstearyl alcohol and the thickening agent hydroxyl propyl methylcellulose. Additionally, the influence of pH, the presence of the antioxidant, alpha-tocopherol, as well as the chelating agent, disodium edetate, on the stability of the formulation have been investigated. Trial drug product formulations, which were designed to investigate the influence of the above-mentioned components/parameters were manufactured and their stability was tested according to current ICH Guidelines. The content, purity and crystalline structure of the active substance in these formulations was analyzed by a combination of HPLC and microscopy techniques. The study demonstrates that the rate of isomerization of betamethasone valerate depends significantly on the concentration of emulsifier used in the cream formulation. At higher concentrations of emulsifier the isomerization proceeds rapidly with significant degradation over a period of weeks, whereas at lower concentrations significant degradation may not be observed, even after several years’ storage. The influence of the emulsifier has been shown to be independent of the pH value of the aqueous phase of the cream. These findings have not been reported in previous literature reports on this topic, which have tended to focus on the influence of pH. The results are likely to be of interest to pharmaceutical chemists working on the formulation of glucocorticoids as well as to local- and hospital pharmacists who carry out the practice of dilution of proprietary corticoid preparations, where the choice of diluent is likely to be critical for ensuring the stability of the diluted product.

Material and Compression Properties of Cedrela odorata Gum Co-Processed with Plantain Starch and Microcrystalline Cellulose.

Many excipients used in tableting exhibit some undesirable properties such as poor flow, cohesion and lubricating characteristics, thus necessitating some modification to achieve the desired product. The objective of this study was to enhance the material, flow and compressional properties of Cedrela odorata gum (COG) (Family: Meliaceae) by co-processing with plantain starch (PS) and microcrystalline cellulose (MCC). The COG was co-processed with PS (or MCC) by physical co-grinding at ratio 1 : 1, 1 : 2 and 1 : 4, and characterized using morphological analysis, swelling index viscosity measurements, particle size analysis and FTIR spectra. The material, flow and compressional properties of the co-processed excipients were also evaluated. Results were analyzed using mean and standard deviation of data. There was a decrease in the degree of agglomeration of COG and a reduction in the size of the powdered gum. The co-processed excipients were more spherical than the native excipients. The COG had the highest viscosity, while MCC and COG : PS (1 : 2) showed the highest and lowest degrees of swelling at 27.0 ± 0.05°C respectively. Water absorption capacity of the component excipients improved with co-processing COG : MCC increasing from 171.8 ± 1.54 (1 : 1) to 214.8 ± 1.07 (1 : 2), while COG : PS increased from 95.2 ± 0.08 (1 : 1) to 206.2 ± 0.13. There was a decrease in the percentage solubility of the co-processed excipients with the highest and lowest solubility observed in COG (54.1 ± 0.07%) and PS (3.7 ± 0.16%), respectively. The FTIR spectra indicate no significant interaction between the excipients. The poor flow of the component excipients did not improve with co-processing; however, there was a significant increase in compressibility. Generally, COG co-processed with MCC showed better compression properties when compared with COG co-processed with PS. Co-processing of COD with MC or PS enhanced the characters of the component excipients, thus making the co-processed excipients suitable for direct compression of tablets without altering the chemical nature of the component excipients.

Influence of the Component Excipients on the Quality and Functionality of a Transdermal Film Formulation.

The influence of formulation variables, i.e., a hydrophilic polymer (Methocel(®) E15) and a film-forming polymer (Eudragit(®) RL 100 and Eudragit(®) RS 100), on the physicochemical and functional properties of a transdermal film formulation was assessed. Several terpenes were initially evaluated for their drug permeation enhancement effects on the transdermal film formulations. D-Limonene was found to be the most efficient permeation enhancer among the tested terpenes. Transdermal film formulations containing granisetron (GRN) as a model drug, D-limonene as a permeation enhancer, and different ratios of a hydrophilic polymer (Methocel(®) E15) and a film-forming polymer (Eudragit(®) RL 100 or Eudragit(®) RS 100) were prepared. The prepared films were evaluated for their physicochemical properties such as weight variation, thickness, tensile strength, folding endurance, elongation (%), flatness, moisture content, moisture uptake, and the drug content uniformity. The films were also evaluated for the in vitro drug release and ex vivo drug permeation. The increasing ratios of Methocel(®):Eudragit(®) polymers in the formulation linearly and significantly increased the moisture content, moisture uptake, water vapor transmission rate (WVTR), and the transdermal flux of GRN from the film formulations. Increasing levels of Methocel(®) in the formulations also increased the rate and extent of the GRN release and the GRN permeation from the prepared films.

Micropreparative isolation and NMR structure elucidation of metabolites of the drug candidate 1-isopropyl-4-(4-isopropylphenyl)-6-(prop-2-yn-1-yloxy) quinazolin-2(1H)-one from rat bile and urine.

LC-MS based drug metabolism studies are effective in the optimization stage of drug discovery for rapid partial structure identification of metabolites. However, these studies usually do not provide unambiguous structural characterization of all metabolites, due to the limitations of MS-based structure identification. LC-MS-SPE-NMR is a technique that allows complete structure identification, but is difficult to apply to complex in vivo samples (such as bile collected during in vivo drug metabolism studies) due to the presence, at high concentrations, of interfering endogenous components, and potentially also dosage excipient components (e.g. polyethylene glycols). Here, we describe the isolation and structure characterization of seven metabolites of the drug development candidate 1-isopropyl-4-(4-isopropylphenyl)-6-(prop-2-yn-1-yloxy) quinazolin-2(1H)-one from a routine metabolism study in a bile-duct cannulated rat by LC-MS-SPE. The metabolites were isolated from bile and urine by repeated automatic trapping of the chromatographic peak of each metabolite on separate Oasis HLB SPE columns. The micropreparative HPLC/MS was performed on an XBridge BEH130 C18 HPLC column using aqueous formic acid/acetonitrile/methanol as mobile phase for the gradient elution. Mass spectrometric detection was performed on a LTQ XL linear ion trap mass spectrometer using electrospray ionization. Desorption of each metabolite was performed after the separation sequence. NMR spectra ((1)H, (13)C, 2D ROESY, HSQC and HMBC were measured on a Bruker AVANCE III spectrometer (600 MHz proton frequency) equipped with a 1.7 mm (1)H{(13)C,(15)N} Bruker Biospin's TCI MicroCryoProbe™.