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.

Selective laser sintering 3D printing - an overview of the technology and pharmaceutical applications.

Food and Drug Administration (FDA) has approved a drug product (Spritam®) and many medical devices manufactured by three-dimensional printing (3DP) processes for human use. There is immense potential to print personalized medicines using 3DP. Many 3DP methods have been reported in the literature for pharmaceutical applications. However, selective laser sintering (SLS) printing has remained least explored for pharmaceutical applications. There are many advantages and challenges in adopting a SLS method for fabrication of personalized medicines. Solvent-free nature, availability of FDA approved thermoplastic polymer/excipients (currently used in hot melt-extrusion process), minimal/no post-processing step, etc. are some of the advantages of the SLS printing process. Major challenges of the technology are requirement of at least one thermoplastic component in the formulation and thermal stability of drug and excipients. This review provides an overview of the SLS printing method, excipient requirements, process monitoring, quality defects, regulatory aspects, and potential pharmaceutical applications.

Lesson Learnt from Recall of Valsartan and Other Angiotensin II Receptor Blocker Drugs Containing NDMA and NDEA Impurities.

The presence of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in angiotensin II receptor blocker (ARB) drugs containing tetrazole ring has triggered worldwide product recalls. The purpose of this article is to identify the potential gap area in current pharmaceutical industry practice that might have led to the NMDA and NDEA impurities escaping the drug manufacturer's and FDA's attention. The impact of process change was not adequately assessed by the manufacturer of contaminated APIs (active pharmaceutical ingredients), and potential for generation of mutagenic or other toxic impurities was not considered. The safety and risk associated with a chemical synthetic process was also not evaluated. This is primarily due to current industry practice which focuses on controlling the impurities above reporting threshold. ICH Q3A and FDA guidance on genotoxic and carcinogenic impurities in drug substances and products need to be integrated so that the ICH Q3A decision tree (attachment 3) begins by checking whether the synthetic process has been evaluated for the potential to generate toxic impurities. The compliance with ICH Q3A limits should be carried out only after the process has been determined to be safe without the risk of generating mutagenic and carcinogenic impurities.

Integrating biopharmaceutics risk assessment and in vivo absorption model in formulation development of BCS class I drug using the QbD approach.

OBJECTIVE: Clinically relevant critical quality attributes (CQA's) were identified for the development of generic drug products containing fluconazole and potential design spaces relevant to the clinical application of the drug candidate was explored. SIGNIFICANCE: A simplified scoring system for the biopharmaceutics risk assessment roadmap (BioRAM) is proposed to guide product development. METHODS: Factorial design of experiments was employed to study the effect of formulation and process variables on CQA's. The in vivo model was developed for predicting the fraction of drug absorbed and to identify the effect of formulation components on drug absorption. RESULTS: BioRAM yielded low scores for fluconazole absorption with respect to severity (risks of sub and supra-bioavailable drug products), probability of incidence of bioinequivalent results and capacity of detection. The results demonstrated that dissolution was highly influenced by the active pharmaceutical ingredient (API) polymorphism and the ratio of diluents. Process variables (mixing time, lubricant concentration, lubrication time and filling speed) did not impact the clinical outcome of the formulation with respect to dissolution and content uniformity. CONCLUSIONS: Understanding the clinical implications of the adopted formulation approach led to the construction of purposeful design space and control strategy.

Pediatric drug development: formulation considerations.

Absence of safe, effective and appropriate treatment is one of the main causes of high mortality and morbidity rates among the pediatric group. This review provides an overview of pharmacokinetic differences between pediatric and adult population and their implications in pharmaceutical development. Different pediatric dosage forms, their merits and demerits are discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical companies to perform pediatric clinical studies on new drug products. Drug development program should include additional clinical bridge studies to evaluate differences in pharmacokinetics and pharmacodynamics of drugs in adult and child populations. Additionally, pharmaceutical development should consider ease of administration, palatability, appropriate excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population is diverse with individual preferences and demand for custom made dosage formulations. Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted.

Temperature-mediated absorption of phenylmercuric nitrate on polyethylene and polypropylene containers in chloramphenicol eye drops.

The aim of this work was to find the effect of temperature and manufacturing source of phenylmercuric nitrate (PMN) on PMN absorption on low-density polyethylene (LDPE) and polypropylene containers in chloramphenicol eye drops. Two factorial experiments were designed to study the effect of temperature on PMN assay in chloramphenicol eye drops stored in LDPE and prepared from two different PMN sources. PMN source had no effect on PMN assay at 2-8 °C, however at stress conditions (30 °C/75%RH) for 3 weeks, the effect of PMN source on PMN assay was found significant (p < 0.05) in formulations stored in LDPE bottles. Temperature was the major contributor to decreased PMN assay. In formulations stored in polypropylene containers, PMN source had significant effect on PMN assay at 2-8 °C and 30 °C/75%RH. Overall, new PMN and polypropylene bottles performed better. The eye drops complied with preservative efficacy test both initially and at the end of shelf life. The concentration exponent of PMN is very low and in spite of its high absorption by container/closure, PMN was still able to protect the eye drops at the end of shelf life. It can be inferred that preservative efficacy test is the better indicator of preservative activity.

Tulsi oil as a potential penetration enhancer for celecoxib transdermal gel formulations.

The focus of the present study was to develop and evaluate the transdermal system of celecoxib. Transdermal gels composed of carbopol 940 in propylene glycol (PG) containing penetration enhancers. The formulations were characterized by permeation, pharmacokinetics, pharmacodynamics and histopathology. Celecoxib permeation across excised rat skins were statistically (p < 0.05) enhanced by tulsi oil compared to turpentine oil containing formulations. In comparison to orally administered formulations, the pharmacokinetic parameters of gel and control formulations were significantly higher (p < 0.05). The maximum plasma concentration (Cmax) obtained with formulations containing 4% turpentine and 6% tulsi oil was, respectively, 1.52 and 2.41 times higher than the formulations without penetration enhancer. Similarly, area under the curve (AUC) of these formulations was 1.70 and 2.40 times higher than the formulations without penetration enhancers. Anti-inflammatory studies demonstrated a statistically significant (p < 0.05) pharmacodynamics profile for the transdermal gel formulations compared to orally administered and control celecoxib formulations. Histopathological studies revealed some disruption in the epidermis without any toxic effect on the dermis layer of skin by penetration enhancers. In summary, the transdermal gel formulations of celecoxib containing penetration enhancers sustained drug level in the blood and will reduce the dose frequency as required with its conventional oral formulation.

Comparative binding and disintegrating property of Echinochloa colona starch (difra starch) against maize, sorghum, and cassava starch.

CONTEXT: Starch obtained from different botanical sources exhibit different characteristics due to variation in amylase-amylopectin ratio, which results in different binder substrate interactions. OBJECTIVE: The present study characterized Echinochloa colona (L.) Link (Poaceae) starch and evaluated its compressional characteristics for use as tablet excipient against commonly used maize, sorghum, and cassava starch. MATERIALS AND METHODS: Three experimental design studies were performed to determine the effects of the maize starch and povidone on physical properties of paracetamol (250 mg) tablets. The effect of superdisintegrants sodium starch glycolate and croscarmellose sodium on the optimized composition obtained in the preceding experiments was evaluated in two factorial experimental studies. The maize starch in the optimum formulations was replaced with difra, sorghum, and cassava starch, and tablets prepared from these starches were compared for their compressional characteristics, lubrication sensitivity, moisture uptake, and drug release. RESULTS: Tablets prepared from maize starch and povidone (30:9, w/w) blend which was previously mixed for 8 min disintegrated (DT) in 10 min. Superdisintegrants decreased DT of tablets significantly (p < 0.05) to 2.2 min. The Hausner ratios of co-processed mixtures containing sorghum, maize, and difra starch were 1.19, 1.21, and 1.26, respectively, with equilibrium moisture content of 8-9%. The DT of sorghum and difra starch formulations which related directly to their higher hydration capacity (difra > sorghum > maize starch) and swelling property was 1.5 min and 2.5 min, respectively, with a friability of 0.32%. The effect of lubrication on the DT and friability of tablets containing maize and difra starch was significant (p < 0.05). However, more than 90% drug was released in vitro dissolution studies. CONCLUSION: Difra starch can replace maize and sorghum starch as tablet excipient.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Isavuconazonium Sulfate.

A Biopharmaceutics Classification System (BCS)-based biowaiver monograph is presented for isavuconazonium sulfate. A BCS-based biowaiver is a regulatory option to substitute appropriate in vitro data for in vivo bioequivalence studies. Isavuconazonium sulfate is the prodrug of isavuconazole, a broad-spectrum azole antifungal indicated for invasive fungal infections. While the prodrug can be classified as a BCS Class III drug with high solubility but low permeability, the parent drug can be classified as a BCS Class II drug with low solubility but high permeability. Interestingly, the in vivo behavior of both is additive and leads isavuconazonium sulfate to act like a BCS class I drug substance after oral administration. In this work, experimental solubility and dissolution data were evaluated and compared with available literature data to investigate whether it is feasible to approve immediate release solid oral dosage forms containing isavuconazonium sulfate according to official guidance from the FDA, EMA and/or ICH. The risks associated with waiving a prodrug according to the BCS-based biowaiver guidelines are reviewed and discussed, noting that current regulations are quite restrictive on this point. Further, results show high solubility but instability of isavuconazonium sulfate in aqueous media. Although experiments on the dissolution of the capsule contents confirmed 'very rapid' dissolution of the active pharmaceutical ingredient (API) isavuconazonium sulfate, its release from the commercial marketed capsule formulation Cresemba is limited by the choice of capsule shell material, providing an additional impediment to approval of generic versions via the BCS-Biowaiver approach.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Fexofenadine.

In this monograph, the potential use of methods based on the Biopharmaceutics Classification System (BCS) framework to evaluate the bioequivalence of solid immediate-release (IR) oral dosage forms containing fexofenadine hydrochloride as a substitute for a pharmacokinetic study in human volunteers is investigated. We assessed the solubility, permeability, dissolution, pharmacokinetics, pharmacodynamics, therapeutic index, bioavailability, drug-excipient interaction, and other properties using BCS recommendations from the ICH, FDA and EMA. The findings unequivocally support fexofenadine's classification to BCS Class IV as it is neither highly soluble nor highly permeable. Further impeding the approval of generic equivalents through the BCS-biowaiver pathway is the reference product's inability to release ≥ 85 % of the drug substance within 30 min in pH 1.2 and pH 4.5 media. According to ICH rules, BCS class IV drugs do not qualify for waiving clinical bioequivalence studies based on the BCS, even though fexofenadine has behaved more like a BCS class I/III than a class IV molecule in pharmacokinetic studies to date and has a wide therapeutic index.

Quality risk management in pharmaceutical development.

The objective of ICH Q8, Q9 and Q10 documents is application of systemic and science based approach to formulation development for building quality into product. There is always some uncertainty in new product development. Good risk management practice is essential for success of new product development in decreasing this uncertainty. In quality by design paradigm, the product performance properties relevant to the patient are predefined in target product profile (TPP). Together with prior knowledge and experience, TPP helps in identification of critical quality attributes (CQA's). Initial risk assessment which identifies risks to these CQA's provides impetus for product development. Product and process are designed to gain knowledge about these risks, devise strategies to eliminate or mitigate these risks and meet objectives set in TPP. By laying more emphasis on high risk events the protection level of patient is increased. The process being scientifically driven improves the transparency and reliability of the manufacturer. The focus on risk to the patient together with flexible development approach saves invaluable resources, increases confidence on quality and reduces compliance risk. The knowledge acquired in analysing risks to CQA's permits construction of meaningful design space. Within the boundaries of the design space, variation in critical material characteristics and process parameters must be managed in order to yield a product having the desired characteristics. Specifications based on product and process understanding are established such that product will meet the specifications if tested. In this way, the product is amenable to real time release, since specifications only confirm quality but they do not serve as a means of effective process control.

Data integrity issues in pharmaceutical industry: Common observations, challenges and mitigations strategies.

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.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Levocetirizine Dihydrochloride.

Levocetirizine, a histamine H1-receptor antagonist, is prescribed to treat uncomplicated skin rashes associated with chronic idiopathic urticaria as well as the symptoms of both seasonal and continual allergic rhinitis. In this monograph, the practicality of using Biopharmaceutics Classification System (BCS) based methodologies as a substitute for pharmacokinetic studies in human volunteers to appraise the bioequivalence of immediate-release (IR) oral, solid dosage forms containing levocetirizine dihydrochloride was investigated, using data from the literature and in-house testing. Levocetirizine's solubility and permeability properties, as well as its dissolution from commercial products, its therapeutic uses, therapeutic index, pharmacokinetics and pharmacodynamic traits, were reviewed in accordance with the BCS, along with any reports in the literature about failure to meet bioequivalence (BE) requirements, bioavailability issues, drug-excipient interactions as well as other relevant information. The data presented in this monograph unequivocally point to classification of levocetirizine in BCS Class 1. For products that are somewhat supra-equivalent or somewhat sub-equivalent, clinical risks are expected to be insignificant in light of levocetirizine's wide therapeutic index and unlikelihood of severe adverse effects. After careful consideration of all the information available, it was concluded that the BCS-based biowaiver can be implemented for products which contain levocetirizine dihydrochloride, provided (a) the test product comprises excipients that are typically found in IR oral, solid drug products that have been approved by a country belonging to or associated with ICH and are used in quantities that are typical for such products, (b) data supporting the BCS-based biowaiver are gathered using ICH-recommended methods, and (c) all in vitro dissolution requirements specified in the ICH guidance are met by both the test and comparator products (in this case, the comparator is the innovator product).

Hyperpigmentation: Looking beyond hydroquinone.

Hyperpigmentation is the most common complaint in the age group 40-45 years, seeking consultation for skin disorders. Hydroquinone is a commonly used depigmenting agent in clinical practice for treating hyperpigmentation. Prolonged use of hydroquinone has been associated with cancer risk and exogenous ochronosis. The CARES (The Coronavirus Aid, Relief, and Economic Security Act) Act of 2020 has instituted significant changes to hydroquinone containing OTC (over the counter) products, and consequently, many hydroquinone-based OTC products had to be withdrawn from the market. Henceforth, products containing hydroquinone would need US Food and Drug Administration approval via new drug application pathways for commercialization. Alternative treatment options to hydroquinone in clinical practice are reviewed in this paper with regard to their safety and efficacy vis a vis hydroquinone. Also, new potential treatment options such as thiamidol, Polypodium leucotomos, and glutathione are discussed. The review shows that these alternative depigmenting agents can be rationally combined to achieve desired treatment goals in the management of hyperpigmentation.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Sitagliptin Phosphate Monohydrate.

Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms containing sitagliptin phosphate monohydrate, as an alternative to a pharmacokinetic study in human volunteers. The solubility and permeability characteristics of sitagliptin were reviewed according to the BCS, along with dissolution, therapeutic index, therapeutic applications, pharmacokinetics, pharmacodynamic characteristics, reports of bioequivalence (BE) / bioavailability problems, data on interactions between the drug and excipients and other data germane to the subject. All data reviewed in this monograph unambiguously support classification of sitagliptin as a BCS Class 1 drug. In light of its broad therapeutic index and lack of severe adverse effects, the clinical risks associated with moderately supraoptimal doses were deemed inconsequential, as were the risks associated with moderately suboptimal doses. Taking all evidence into consideration, it was concluded that the BCS-based biowaiver can be implemented for solid IR oral drug products containing sitagliptin phosphate monohydrate, provided (a) the test product is formulated solely with excipients commonly present in solid IR oral drug products approved in ICH or associated countries and used in amounts commonly applied in this type of product, (b) data in support of the BCS-based biowaiver are obtained using the methods recommended by the WHO, FDA, EMA or ICH and (c) the test product and the comparator product (which is the innovator product in this case) meet all in vitro dissolution specifications provided in the WHO, FDA, EMA or ICH guidance.

Converging Generic Drug Product Development: Bioequivalence Design and Reference Product Selection.

Different regulatory agencies provide criteria for selecting a reference product for bioequivalence (BE) studies. In most cases, the criteria vary from one regulatory agency to another, and, consequently, the generic companies often have to repeat the BE studies comparing the same test product with the reference product purchased from a particular country. In addition to being a cost-intensive exercise, this practice is also unethical. The purpose of this article is to discuss the current policy of major regulatory authorities on the selection of the reference product for pharmaceutical equivalence (PE) and BE studies, the cost implications of such regulatory practices, and to also explore the opportunity to harmonize the reference product selection criteria for reducing repetitive BE studies. The regulatory guidance documents of major jurisdictions are reviewed for similarities and differences in generic product definition, BE study design and conduct, and reference product selection criteria for PE and BE studies. A case study is presented to understand how harmonisation can be achieved and how the economic benefits of this harmonisation cannot be underestimated. Harmonisation in reference product selection criteria can pave the way for a common BE study(s) that would be acceptable to the majority of regulatory agencies, and would not only significantly reduce operating costs but would also minimize the exposure of healthy human beings to drugs.

Integrating QbD Tools for Flexible Scale-Up Batch Size Selection for Solid Dosage Forms.

The pilot scale batch size for solid oral dosage forms is currently defined by major regulatory agencies as one-tenth of the full production, or 100,000 units, whichever is larger. The current criterion is arbitrary and is not based on scientific and risk assessment principles. The approach does not consider geometric, kinematic, and dynamic changes that come into play on scale-up. Even if this criterion is met, impact of scale-up on critical quality attributes cannot be ruled out and also reproducibility cannot be assured simply by restricting the scale-up size. In keeping with the vision for the 21st Century Good Manufacturing Practice initiative to build quality into the product, it is imperative that the selection of scale-up batch size be based on science and risk assessment principles and be part of the product development program. Scale-up should never be seen as an isolated activity. This article will review various tools that can be integrated with quality by design for flexible batch size selection during scale-up.

Biowaiver Monograph for Immediate-Release Solid Oral Dosage Forms: Moxifloxacin Hydrochloride.

In this monograph, literature data is reviewed to evaluate the feasibility of waiving in vivo bioequivalence testing and instead applying the Biopharmaceutics Classification System (BCS) based methods to the approval of immediate-release solid oral dosage forms containing moxifloxacin hydrochloride as the sole active pharmaceutical ingredient. To facilitate the feasibility decision, solubility and permeability and dissolution characteristics in the context of the BCS, therapeutic index, therapeutic use, pharmacokinetic parameters, bioequivalence/bioavailability issues, drug-excipient interactions and other relevant data were taken into consideration. Moxifloxacin is a BCS class I drug with a wide therapeutic index. Bioequivalence risks arising from the presence of different excipients in the formulation and due to manufacturing variables were deemed to be low. The risks can be further reduced if the choice of excipients is limited to those present in products already approved in International Conference on Harmonisation or associated countries and if the results of in vitro dissolution studies comply with the specifications stipulated in the appropriate biowaiver guidelines. Under these conditions, we conclude that a BCS-based biowaiver can be recommended for moxifloxacin immediate-release solid oral dosage forms.

In-vivo evaluation in rats of colon-specific microspheres containing 5-fluorouracil.

The aims of this investigation were to determine the distribution in the gastrointestinal (GI) tract of Eudragit S-100 encapsulated colon-specific sodium alginate microspheres containing 5-fluorouracil (5-FU) in rats, and to perform pharmacokinetic and pharmacodynamic studies. Comparisons were with a control immediate-release (IR) formulation of 5-FU. 5-FU was distributed predominantly in the upper GI tract from the IR formulation but was distributed primarily to the lower part of the GI tract from the microsphere formulation. No drug was released in the stomach and intestinal regions from the colon-specific microspheres. Significantly, a high concentration of the active drug was achieved in colonic tissues from the colon-specific microspheres (P < 0.001), which was higher than the IC50 required to halt the growth of and/or kill colon cancer cells. Colon cancer was induced in rats by subcutaneous injection of 1,2-dimethylhydrazine (40 mg kg (-1)) for 10 weeks. The tumours induced were non-invasive adenocarcinomas and were in Duke's stage A. The 5-FU formulations were administered for 4 weeks after tumour induction. Non-significant reductions in tumour volume and multiplicity were observed in animals given the colon-specific microspheres. Enhanced levels of liver enzymes (SGOT, SGPT and alkaline phosphatase) were found in animals given the IR formulation of 5-FU, and values differed significantly (P < 0.001) from those in animals treated with the colon-specific microspheres. Elevated levels of serum albumin and creatinine, and leucocytopenia and thrombocytopenia were observed in the animals given the IR formulation. In summary, Eudragit S-100 coated alginate microspheres delivered 5-FU to colonic tissues, with reduced systemic side-effects. A long-term dosing study is required to ascertain the therapeutic benefits.

Improvement in bioavailability of transdermally applied flurbiprofen using tulsi (Ocimum sanctum) and turpentine oil.

Penetration enhancing potential of tulsi and turpentine oil on transdermal delivery of flurbiprofen, a potent non-steroidal anti-inflammatory agent, was investigated. The transdermal permeation rate of flurbiprofen across the rat abdominal skin from binary solvent mixture composition of propylene glycol (PG):isopropyl alcohol (IPA) (30:70%, v/v) was 98.88 microg/cm(2)/h, significantly higher than other binary solvent mixtures. The corresponding steady state plasma concentration, 0.71 microg/ml, was much lower than required steady state plasma concentration of 3-5 microg/ml. Hence influence of tulsi and turpentine oil in the optimized binary solvent mixture along with the increased drug load on the flurbiprofen permeation was evaluated. The magnitude of the flux enhancement factor with turpentine oil and tulsi oil was 2.4 and 2.0 respectively at 5% (v/v) concentration beyond which there was no significant increase in the flux. Addition of 2% (w/v) hydroxypropyl methylcellulose (HPMC), as a thickening agent, resulted in desired consistency for the fabrication of patch with insignificant effect on permeation rate of flurbiprofen. The reservoir type of transdermal patch formulation, fabricated by encapsulating the flurbiprofen reservoir solution within a shallow compartment moulded from polyester backing film and microporous ethyl vinyl acetate membrane, did not modulate the skin permeation of flurbiprofen through rat skin in case of turpentine formulations whereas flux of formulations with tulsi oil was significantly altered. The influence of penetration enhancer and solvents on the anatomical structure of the rat skin was studied. Enhancement properties exhibited by turpentine oil and tulsi oil in optimized binary solvent mixture were superior as compared to solvent treated and normal control groups with negligible skin irritation. The fabricated transdermal patches were found to be stable. The bioavailability of flurbiprofen with reference to orally administered flurbiprofen in albino rats was found to increase by 2.97, 3.80 and 5.56 times with transdermal patch formulation without enhancer, tulsi and turpentine oil formulations, respectively. The results were confirmed by pharmacodynamic studies in rat edema inflammation model.