In Vitro Tools for Evaluating Novel Dosage Forms of Poorly Soluble,Weakly Basic Drugs: Case Example Ketoconazole

The aim of the present series of experiments was to compare various in vitro tools including evaluation of formulations influence on solubility, various dissolution tests, and an updated, miniaturized transfer model to forecast the behavior of novel formulations of the poorly soluble, weakly basic model compound ketoconazole (KETO) after oral administration. A binary complex with hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) and a ternary formulation with HP‐β‐CD and Soluplus® were evaluated and their solubility, dissolution, and transfer behavior was compared with that of the pure drug. Binary and ternary formulations could significantly improve (p < 0.05) KETO solubility in all test media. Dissolution in media simulating the fasted stomach and the fed small intestine was almost complete for the pure drug and both complex formulations. By contrast, in pH 6.5 FaSSIF, dissolution of the pure drug was less than 10%. Both formulations resulted in significantly higher KETO release (p < 0.05) in this test medium (32%/95% release from the binary/ternary formulation). In the transfer experiments, the ternary complex showed the best performance with respect to stabilizing a supersaturated solution and inhibiting precipitation of KETO. Overall, the miniaturized transfer model appeared to be the best single tool for rank‐ordering formulations.     

Development and evaluation of febuxostat solid dispersion through screening method

Febuxostat (Febux) is a BCS II drug and has a very low solubility. In order to overcome this shortcoming, the purpose of study is to increase the in vitro dissolution (%) and drug release (%) of Febux by using a screening method. The Febux-SD formulation was prepared by screening solubilizers, pH agents, and carriers using with a solvent evaporation method.The novel Febux SD formulation was successfully developed. The dissolution (%) of Febux of optimal formulation (SD3) was higher than that of Feburic® tab in pH 1.2, distilled water (DW), and pH 6.8 buffer by 6.3-, 2.6-, and 1.1-fold, respectively, at 60 min. The in vitro drug release (%) and permeability (μg/cm²) of SD3 formulation were improved compared to those of Feburic® tab in the pH shifting method and PBS (7.4), respectively. The SD3 formulation was well maintained the stability for 6 months, and that of physicochemical properties were altered. In conclusion, the Febux solubilization study with meglumine was first attempted and successfully performed. Through the improved dissolution (%) of Febux, high bioavailability of SD3 formulation is expected in animal and human studies.     

阿瑞匹坦三元超饱和固体分散体的制备及性能考察

目的：为了提高难溶性药物阿瑞匹坦(Aprepitant,APR)的溶解度,解决其酸中溶出、碱中结晶沉淀的问题,选择不同功能的聚合物载体,采用热熔挤出技术制备三元固体分散体,并对其进行性能考察;方法：采用溶剂-熔融法制备二元固体分散体,以溶出度和溶出速度为指标,筛选具有增溶功能的载体材料。通过介质转移法考察各聚合物在不同浓度的药物溶液中的抑晶性能,筛选出最佳的沉淀抑制剂。确定药载比,将APR、溶出促进剂及沉淀抑制剂以不同比例混合,采用热熔挤出技术制备三元固体分散体,以溶出度和抑晶时间为指标,优选出三元固体分散体处方。经XRD确认药物在载体中的存在状态,考察该三元固体分散体在模拟肠液中的动态溶解度和加速条件下的物理稳定性。结果：亲水性聚合物PVP K30制备的二元固体分散体溶出速度快,增溶效果佳,肠溶性聚合物HPMCAS显示出优越的抑晶作用,延长了APR的过饱和点,质量比为1:1:3(APR:PVP K30:HPMCAS)的三元固体分散体在酸中迅速完全释放(120min溶出95%),相对于原料药显著提高了溶出度和溶出速率,当介质pH转为6.8后,三元固体分散体完全释放并在6h内维持溶液处于高过饱和的稳定状态,药物以无定形形式存在于载体基质中,同时能在加速条件下保持至少三个月的无定形状态。结论：基于不同聚合物的理化特性,本研究制备的三元固体分散体通过协调溶出速率和结晶抑制效果,不仅显著提高APR的溶解度,并能解决APR在胃中溶出、肠中沉淀析晶的问题,具有良好的溶出特性。     

Study on solubility improvement of lidocaine by ternary solid dispersion

In the present study, we aimed to probe the possibility of using mixed poloxamers as carriers to prepare ternary solid dispersion (SD) that facilitated solubility and dissolution rate of the poorly water soluble drug and compare with binary SD with single poloxamer. Lidocaine (LIC) was selected as a model drug, and poloxamer 188 (P188) and poloxamer 407 (P407) were utilized as single and mixed carriers. Depending on DSC and the dissolution testing, the appropriate ratio of SD prepared by melting method was optimized. Ternary and binary SD was characterized by DSC, XRD, SEM and FTIR. In vitro dissolution study, phase solubility study and saturated solubility study were performed to clarify solubilization from apparent phenomena and inherent reason. Moreover, stability study under different relative humidity (RH) was investigated. Physical characterizations of binary and ternary SD exhibited the formation of eutectic mixture and the presence of molecular interaction. Compared with the pure LIC, the dissolution rate and solubility of LIC in binary and ternary SDs were enhanced. The phase solubility study revealed an AL-type curve. Furthermore, the stability test indicated that ternary and binary SD was stable. The results of this study demonstrated that SD with mixed poloxamers could improve dissolution rate and solubility of poorly water-soluble drug.     

Bioavailability enhancement of poorly water soluble and weakly acidic new chemical entity with 2-hydroxy propyl-beta-cyclodextrin: selection of meglumine, a polyhydroxy base, as a novel ternary component

The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The molecular inclusion of DRF-4367 with HPbetaCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPbetaCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPbetaCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPbetaCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension.     

Amorphous ternary cyclodextrin nanocomposites of telmisartan for oral drug delivery: Improved solubility and reduced pharmacokinetic variability

Despite of advancements in dosage form design and use of multifunctional excipients, improvement in dissolution characteristics of molecules like Telmisartan (TEL) having exceedingly pH dependent and poor solubility profile is still challenging. The present research work explores an innovative particle engineering approach which synergistically coalesce two principally different solubility enhancement strategies namely ternary β-cyclodextrin complexation and top-down nanonization in a unit process. The research was aimed to improve solubility and reduce in vivo variability in pharmacokinetic parameters of TEL irrespective to physiological pH conditions. Ternary β-cyclodextrin nanocomposites of TEL were prepared with high pressure homogenization using meglumine as ternary component. TEL nanocomposites were thoroughly characterized for particle size, surface topology, surface charge, inclusion complexation, crystalinity, dissolution and in vivo pharmacokinetic performance in male wistar rats at fed and fasted state. TEL nanocomposites exhibited average particle size of 698 ± 23 nm. Remarkable improvement in in vitro dissolution characteristics in multimedia and biorelevant media was observed in comparison with plain drug and marketed formulation. Results of in vivo pharmacokinetic studies revealed that, nanocomposites effectively bypass variation in pharmacokinetic parameters at fed and fasted states with 346%, 315%, 301% and 321% increase in relative bioavailability compared to marketed formulation and pure TEL in fed and fasted conditions respectively.     

Solubilization of a Poorly Soluble B-Raf (Rapidly Accelerated Fibrosarcoma) Inhibitor: From Theory to Application

The oral bioavailability of a drug candidate is influenced by its permeability, metabolism, and physicochemical properties. Among the physicochemical properties, solubility and dissolution rate often are the most critical factors affecting the oral bioavailability of a compound. The increasing challenge for the pharmaceutical industry is to achieve reasonable oral bioavailability of poorly water-soluble drug candidates. G-F is a potent and selective B-Raf (rapidly accelerated fibrosarcoma) inhibitor with poor water solubility and moderate permeability, which resulted in an absorption-limited exposure in preclinical safety studies. The intrinsic solubility of G-F is 8 μg/mL (i.e., 0.0188 nM). In this study, pH adjustment combined with cosolvency, micellization, or complexation was applied as a technique to enhance the solubility of G-F. pH 9.5 and 4 buffers were selected to combine with the solubilization agents based on G-F's acidic pKa of 7.47. The solubilization power of each solubilization agent was determined based on the experimental data. The solubility G-F can be increased up to 4000-fold in a selected combination. The advantage of combination over individual solubilization agent was demonstrated. In this study, the understanding of the solubilization power of each solubilization agent played an important role in the formulation development of this development candidate.     

Mechanistic Basis of Cocrystal Dissolution Advantage

Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development.     

Measurement and correlation of solubility data for albendazole in ten pure solvents and two binary solvent systems from 278.15 K to 323.15 K

The equilibrium solubility of albendazole (ABZ) in ten single solvents and two binary solvent mixtures of different ratio was measured by a typical static method combined with ultraviolet (UV) spectrophotometry within the temperature range from 278.15 K to 323.15 K. Meanwhile, the modified Apelblat model, Van't Hoff equation and λh equation were used to correlate the solubility data of ABZ in pure solvent, the modified Apelblat model, λh equation, Sun model, GSM equation and NRTL model were used to correlate the solubility data of ABZ in binary mixed solvent, the 100RD, 100ARD, 103RMSD and 103ORMSD values of the above models were calculated respectively. The results show that the experimental data of six models have a good correlation with the calculated data. Especially, the Van't Hoff equation in pure solvent has the best fitting effect, and the GSM equation in binary mixed solvent has the best fitting effect. Additionally, the Van't Hoff equation was used to calculate and evaluate the thermodynamic properties of the ABZ dissolution process, including enthalpy (ΔdisH), entropy (ΔdisS) and Gibbs free energy (ΔdisG).     

Formulation Development and Dissolution Rate Enhancement of Efavirenz by Solid Dispersion Systems

The aim of this study was to enhance the dissolution rate of efavirenz using solid dispersion systems (binary and ternary). A comparison between solvent and fusion method was also investigated. Solid dispersions of efavirenz were prepared using polyethylene glycol 8000, polyvinylpyrrolidone K30 alone and combination of both. Tween 80 was incorporated to obtain a ternary solid dispersion system. Dissolution tests were conducted and evaluated on the basis of cumulative percentage drug release and dissolution efficiency. Physicochemical characterizations of the solid dispersions were carried out using differential scanning calorimetric, powder X-ray diffraction, Fourier transform infrared spectroscopy, and scanning electron microscopy. Dissolution was remarkably improved in both systems compared to pure efavirenz (P<0.05). An optimum ratio was identified at a drug:polymer of 1:10. Incorporation of Tween 80 to 1:10 formulations formed using solvent method showed further improvement in the dissolution rate. Physicochemical characterization results suggested that efavirenz existed in the amorphous form in all the solid dispersion systems providing evidence of improvement in dissolution. No statistically significant difference (P>0.05) in dissolution was observed between the two methods. Binary and ternary solid dispersion systems both have showed a significant improvement in the dissolution rate of efavirenz. Formulations with only polyvinylpyrrolidone K30 showed best dissolution profile and 1:10 was identified as an optimum drug-polymer weight ratio.     

Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design,characterization, in vitro and in vivo evaluation

Abstract

Naringenin (NRG), predominant flavanone in grapefruits, possesses anti-inflammatory, anti-carcinogenic, hepato-protective and anti-lipid peroxidation effects. Slow dissolution after oral ingestion due to its poor solubility in water, as well as low bioavailability following oral administration, restricts its therapeutic application. The study is an attempt to improve the solubility and bioavailability of NRG by employing self-nanoemulsifying drug delivery technique. Preliminary screening was carried out to select oil, surfactant and co-surfactant, based on solubilization and emulsification efficiency of the components. Pseudo ternary phase diagrams were constructed to identify the area of nanoemulsification. The developed self-nanoemulsifying drug delivery systems (SNEDDS) were evaluated in term of goluble size, globule size distribution, zeta potential, and surface morphology of nanoemulsions so obtained. The TEM analysis proves that nanoemulsion shows a droplet size less than 50?nm. Freeze thaw cycling and centrifugation studies were carried out to confirm the stability of the developed SNEDDS. In vitro drug release from SNEDDS was significantly higher (p?<?0.005) than pure drug. Furthermore, area under the drug concentration time-curve (AUC_0–24) of NRG from SNEDDS formulation revealed a significant increase (p?<?0.005) in NRG absorption compared to NRG alone. The increase in drug release and bioavailability as compared to drug suspension from SNEDDS formulation may be attributed to the nanosized droplets and enhanced solubility of NRG in the SNEDDS.     

A Modified Approach to Predict Dissolution and Absorption of Polydisperse Powders

Purpose  Particle size of a drug is an important factor that affects thermodynamic solubility and oral absorption of drug molecules. Weight fraction of different particle sizes in a polydisperse powder together with Noyes Whitney parameters (diffusion coefficient, solubility, density of the drug, boundary layer thickness and dissolution volume) can be used to predict dissolution and absorption of drug molecules. Such a simulation can be a valuable tool in setting up guidance with regards to dependence of dissolution and absorption on particle size. Materials and methods  In this note a modified method is reported to predict dissolution of polydisperse drug powder. These use simplified equations developed from a set of differential equations described previously. The idea was to convert all the terms in one single equation which can then be solved by a Matlab program. Conclusion  Discrepancies not reported earlier have been discussed to get the same results as reported previously.     

Effect of physiochemical variables on phase solubility and dissolution behavior of indomethacin solid dispersion system

To study the influence of temperature and pH on solubility and dissolution behavior of indomethacin solid dispersions were prepared using several classes of hydrophilic carriers. Investigations on dissolution of indomethacin in binary system are reported earlier. However the phase solubility and dissolution behavior at different pH and temperature left void. The present investigation includes: phase solubility study at various pH; preparation of solid dispersion by solvent evaporation, melting and kneading method; characterization of various blends by dissolution study, and solid state studies to ensure interaction of drug with carrier. The binding between drug and carriers (PVP K30, βCD and PEG) was explained by thermodynamic parameters as calculated from phase solubility study. Indomethacin in association with PVP K30 showed very high apparent binding constant (Ka) and Gibb’s free energy change (?G) in comparison to other blends. The ternary system (drug:βCD:PVP K30, 1:5:1) showed better dissolution of about 80.97 and 99 % at pH 7.2 after 5 and 30 min respectively. At higher proportion of carrier (1:9) in binary solid dispersion of drug and PVP K30, drug dissolution was 96.23 and 97.85 % after 5 and 30 min respectively. This raised solubility of indomethacin would be helpful in designing a dosage form.     

A new self-emulsifying formulation of mefenamic acid with enhanced drug dissolution

To enhance the dissolution of poorly soluble mefenamic acid, self-emulsifying formulation (SEF), composing of oil, surfactant and co-surfactant, was formulated. Among the oils and surfactants studied, Imwitor^® 742, Tween^® 60, Cremophore^® EL and Transcutol^® HP were selected as they showed maximal solubility to mefenamic acid. The ternary phase diagram was constructed to find optimal concentration that provided the highest drug loading. The droplet size after dispersion and drug dissolution of selected formulations were investigated. The results showed that the formulation containing Imwitor^® 742, Tween^® 60 and Transcutol^® HP (10:30:60) can encapsulate high amount of mefenamic acid. The dissolution study demonstrated that, in the medium containing surfactant, nearly 100% of mefenamic acid were dissolved from SEF within 5 min while 80% of drugs were dissolved from the commercial product in 45 min. In phosphate buffer (without surfactant), 80% of drug were dissolved from the developed SEF within 5 min while only about 13% of drug were dissolved in 45 min, from the commercial product. The results suggested that the SEF can enhance the dissolution of poorly soluble drug and has a potential to enhance drug absorption and improve bioavailability of drug.     

Porous Silica-Supported Solid Lipid Particles for Enhanced Solubilization of Poorly Soluble Drugs

Low dissolution of drugs in the intestinal fluid can limit their effectiveness in oral therapies. Here, a novel porous silica-supported solid lipid system was developed to optimize the oral delivery of drugs with limited aqueous solubility. Using lovastatin (LOV) as the model poorly water-soluble drug, two porous silica-supported solid lipid systems (SSL-A and SSL-S) were fabricated from solid lipid (glyceryl monostearate, GMS) and nanoporous silica particles Aerosil 380 (silica-A) and Syloid 244FP (silica-S) via immersion/solvent evaporation. SSL particles demonstrated significantly higher rate and extent of lipolysis in comparison with the pure solid lipid, depending on the lipid loading levels and the morphology. The highest lipid digestion was observed when silica-S was loaded with 34% (w/w) solid lipid, and differential scanning calorimeter (DSC) analysis confirmed the encapsulation of up to 2% (w/w) non-crystalline LOV in this optimal SSL-S formulation. Drug dissolution under non-digesting intestinal conditions revealed a three- to sixfold increase in dissolution efficiencies when compared to the unformulated drug and a LOV-lipid suspension. Furthermore, the SSL-S provided superior drug solubilization under simulated intestinal digesting condition in comparison with the drug-lipid suspension and drug-loaded silica. Therefore, solid lipid and nanoporous silica provides a synergistic effect on optimizing the solubilization of poorly water-soluble compound and the solid lipid-based porous carrier system provides a promising delivery approach to overcome the oral delivery challenges of poorly water-soluble drugs.     

Bioavailability Enhancement of Poorly Water Soluble and Weakly Acidic New Chemical Entity with 2-Hydroxy Propyl-β-Cyclodextrin: Selection of Meglumine,a Polyhydroxy Base,as a Novel Ternary Component

The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-β-cyclodextrin (HPβCD). The molecular inclusion of DRF-4367 with HPβCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPβCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPβCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPβCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension.     

Cyclodextrin-water soluble polymer ternary complexes enhance the solubility and dissolution behaviour of poorly soluble drugs. Case example: Itraconazole

The aim of the present series of experiments was to improve the solubility and dissolution/precipitation behaviour of a poorly soluble, weakly basic drug, using itraconazole as a case example. Binary inclusion complexes of itraconazole with two commonly used cyclodextrin derivatives and a recently introduced cyclodextrin derivative were prepared. Their solubility and dissolution behaviour was compared with that of the pure drug and the marketed formulation Sporanox®. Ternary complexes were prepared by addition of Soluplus®, a new highly water soluble polymer, during the formation of the itraconazole/cyclodextrin complex. A solid dispersion made of itraconazole and Soluplus® was also studied as a control. Solid state analysis was performed for all formulations and for pure itraconazole using powder X-ray diffraction (pX-RD) and differential scanning calorimetry (DSC). Solubility tests indicated that with all formulation approaches, the aqueous solubility of itraconazole formed with hydroxypropyl-β-cyclodextrin (HP-β-CD) or hydroxybutenyl-β-cyclodextrin (HBen-β-CD) and Soluplus® proved to be the most favourable formulation approaches. Whereas the marketed formulation and the pure drug showed very poor dissolution, both of these ternary inclusion complexes resulted in fast and extensive release of itraconazole in all test media. Using the results of the dissolution experiments, a newly developed physiologically based pharmacokinetic (PBPK) in silico model was applied to compare the in vivo behaviour of Sporanox® with the predicted performance of the most promising ternary complexes from the in vitro studies. The PBPK modelling predicted that the bioavailability of itraconazole is likely to be increased after oral administration of ternary complex formulations, especially when itraconazole is formulated as a ternary complex comprising HP-β-CD or HBen-β-CD and Soluplus®.     

Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of ucb-35440-3, a highly dosed poorly water-soluble weak base

ucb-35440-3 is a new drug entity under investigation at UCB S.A. Due to its physicochemical characteristics, the drug, a poorly water-soluble weak base, shows poor solubility and dissolution characteristics. In rat, the low oral bioavailability (F < 10%) is largely due to poor absorption. In order to enhance the solubility and dissolution characteristics, formulation of ucb-35440-3 as nanocrystals has been achieved in this study. Nanoparticles were prepared using high pressure homogenization and were characterized in terms of size and morphology. In vitro dissolution characteristics were investigated and compared to the un-milled drug in order to verify the theoretical hypothesis on the benefit of increased surface area. In vivo pharmacokinetic evaluation of ucb-35440-3 nanoparticles was also carried out on rats. Crystalline state evaluation before and following particle size reduction was conducted through polarized light microscopy and PXRD to denote any possible transformation to an amorphous state during the homogenization process. Drug chemical stability was also assessed following homogenization. The dissolution rate increased significantly at pH 3.0, 5.0 and 6.5 for ucb-35440-3 nanoparticles. However, the pharmacokinetic profile obtained yielded lower systemic exposure than the un-milled compound (in fed state), this although being thought to be the consequence of the drug and formulation characteristics.     

Development and Validation of Discriminating and Biorelevant Dissolution Test for Lornoxicam Tablets

The establishment of biorelevant and discriminating dissolution procedure for drug products with limited water solubility is a useful technique for qualitative forecasting of the in vivo behavior of formulations. It also characterizes the drug product performance in pharmaceutical development. Lornoxicam, a BCS class-II drug is a nonsteroidal antiinflammatory drug of the oxicam class, has no official dissolution media available in the literature. The objective of present work was to develop and validate a discriminating and biorelevant dissolution test for lornoxicam tablet dosage forms. To quantify the lornoxicam in dissolution samples, UV spectrophotometric method was developed using 0.01M sodium hydroxide solution as solvent at λ_ma×376 nm. After evaluation of saturation solubility, dissolution, sink conditions and stability of lornoxicam bulk drug in different pH solutions and biorelevant media, the dissolution method was optimized using USP paddle type apparatus at 50 rpm rotation speed and 500 ml simulated intestinal fluid as discriminating and biorelevant dissolution medium. The similarity factor (f₂) were investigated for formulations with changes in composition and manufacturing variations, values revealed that dissolution method having discriminating power and method was validated as per standard guidelines. The proposed dissolution method can be effectively applied for routine quality control in vitro dissolution studies of lornoxicam in tablets and helpful to pharmacopoeias.