معرفت طبقات رجال کا تحقیقی جائزہ

According to the traditionists, a Hadith can only be considered reliable when its Sanad offers an unbroken series of credible and veracious authorities till the Prophet Muhammad (S.A.W.). The critical investigation of the Sanad had caused the Muslim Scholars to make thorough research. They endeavored not only to ascertain the names and circumstances of the narrators in order to investigate where and when they lived and which of them had been personally acquainted with the other, but also to test their reliability, truthfulness and accuracy in transmitting the texts, to make certain which of them were reliable. Special works are also devoted to this subject among them many of the so-called Tabqāt works (that is biographies arranged in Islam & Muslims of various scholars). This article develops the concepts and tools for the systematic study of the mechanics of survival for medieval Islamic books. These concepts and tools are then applied to studying the history of the earliest extant biographical dictionary of the Islamic tradition.

In Vitro in Vivo Correlation Studies of Aceclofenac Tablets

Pakistan being a lower middle income country is now facing multiple healthcare issues regarding availability and affordability of drugs. Brand marketing allows the larger access of medicines to the public with restoration of product quality similar to the innovator. Cost effectiveness with desirable excellence is deemed during product development. Selection and levels of excipients greatly characterize the in vitro formulation properties as well as in vivo behavior of drugs. Introduction of Biopharmaceutics Classification System (BCS) has begun a new paradigm for pharmaceutical industries all over the world. It provides a valuable tool in product designing and waiving of in vivo bioequivalence studies. Regulatory authorities put strong emphasis on the determination of various significant pharmacokinetic parameters to assess the bio-similarity of any brand or trial product against innovator. It is estimated that about 22 to 38 million dollars have been saved annually through BCS based biowaiver. In the past few decades, the concept of in vitro in vivo correlation (IVIVC) has gained popularity in different pharmaceutical sectors. IVIVC studies meet the modern challenges of product designing through establishing an association between fraction in vitro drug dissolved and fraction in vivo drug absorbed. The aim of the present study was to develop and optimize aceclofenac trial formulations (100 mg) of various release patterns for IVIVC (Level A) development. Variety of in vitro dissolution media were used to study the drug release behavior. Different model dependent and independent approaches were applied and then bioequivalence study was conducted to compare the test aceclofenac formulation with the reference brand. Aceclofenac is a well known non-steroidal anti-inflammatory drug (NSAID) possessing anti- pyretic, anti-inflammatory and analgesic properties. It is available in oral, topical and parenteral forms. In the present study, immediate (IR), intermediate (IntR) and slow release (SR) trial formulations were prepared using various levels of HPMC K4M, avicel PH 102, and magnesium stearate by direct compression method keeping the aerosil and drug concentration constant. The acdisol (super disintegrant) was only incorporated in IR trial formulations. Central composite rotatable design (CCRD) using Design ExpertTM (version 7) software was used for product optimization. Overall, thirty formulations were evaluated for powder blend properties from immediate, intermediate and slow release formulations. On the basis of good micromeritic attributes nine formulations were chosen, three each from IR (F2, F6, F8), IntR (F13, F17, F19), and SR (F22, F26, F30) for further in vitro characterization. Compressed trial formulations and the reference brand of aceclofenac (Acemed) from a reputable multi-national pharmaceutical industry were exposed to various physicochemical evaluations including weight variation, friability, hardness, disintegration, dissolution, and assay. Drug release was estimated in different dissolution media including hydrochloric acid buffer of pH 1.2, phosphate buffer pH 4.5, and pH 6.8, and biorelevant dissolution media with fasted (FaSSGF and FaSSIF) and fed (FeSSIF) conditions. Influence of surfactants was also observed using SLS and tween 80 since the model drug “aceclofenac” is a BCS class II candidate exhibiting poor solubility. The drug release was significantly increased in presence of surfactants particularly at lower pH values of 1.2 and 4.5. Multi point dissolution test was conducted to study the drug release pattern using model dependent and independent approaches. These models include application of zero order, first order, Higuchi, Korsmeyer-Peppas, Hixon-Crowell, Bakers-Lonsdale and Weibull kinetics. Dissimilarity (f1) and similarity (f2) factors were also assessed to evaluate the closeness of the test formulations against the reference product. Drug release kinetics was computed using a softaware DDSolver an add-in program of Microsoft ExcelTM 2007. Weibull model was found to be the best fitted model in immediate, intermediate and slow release formulations with r2> 0.90 in various pH environments. The stability test was performed as per recommendations of ICH. Optimized formulations were exposed to stress storage conditions to estimate shelf life of the products. Units were removed after specific time intervals and subjected to various quality attributes assessments including friability, hardness, dissolution and assay. Shelf lives of formulations were calculated by stability package R-Gui software (version 3.1.1). All trial formulations were found to be sufficiently stable with no drug degradation and drug-excipient interaction. On the basis of in vitro characterization F8 (IR), F17 (IntR) and F26 (SR) were selected for further in vivo studies. A validated and sensitive isocratic HPLC technique was used to determine assay of optimized products of various releases. The chromatographic conditions were set using reverse phase C18 column (Nucleosil, 250 mm × 4.6 mm × 5 µm, Germany), and a mixture of deionized water and acetonitrile in a proportion of 55:45 as mobile phase with pH adjustment to 2.4 by ortho phosphoric acid (0.01 M). The flow rate was 1mL/min and the detection wave length was 276 nm. The method was found to be sensitive, linear and precised in the range of 50µg/mL to 0.05µg/mL with r2 of 0.999. All other validation parameters were found to be within the acceptable limits both in mobile phase and the plasma. In vivo studies were performed in healthy human male volunteers after informed consent and approval by an independent ethical review committee of Ziauddin University, Karachi, Pakistan (0760513 RBPHARM) and also by the Board of Advanced Studies and Research, University of Karachi. Single dose, four tiers crossover design was used with a washout period of two weeks. Immediate release formulation (F8) and reference brand were given orally and blood samples were collected at time interval of 0, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 7, 9, 10, 12, 14, and 16 hr. While for intermediate release formulation (F17) the blood samples were drawn at time interval of 0, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 16, 18 and 24 hr and 0, 1, 2, 3, 4, 8, 12, 16, 24, 32, 36 and 38 hrs blood sampling was used for slow release (F30). Plasma was separated and after deproteination with acetonitrile, 20µl of the sample was injected and analyzed by HPLC. A software KineticaTM version 5.1 (Thermoelectron, USA) was used for estimation of various in vivo pharmacokinetic parameters. The bioequivalence study of reference and F8 trial formulation showed average values of AUCtotal 21.304 ± 0.305 mg/L×h and 21.866 ± 0.161 mg/L×h, Cmax were 8.599 ± 0.026 µg/mL and 8.629 ± 0.028 µg/mL while Tmax values were 1.472 ± 0.021 hr and 1.460 ± 0.004 hr respectively. Mean clearance and volume of steady state (Vc) of reference formulation were found to be 4.797 ± 0.108 mL/hr/kg and 4.876 ± 0.410 L consecutively. While the corresponding values of clearance and Vc for the three different formulations were 4.861 ± 0.048 mL/hr/kg and 4.801 ± 0.353 L for F8 (IR), 3.388 ± 0.076 mL/hr/kg and 6.462 ± 0.640 L for F17 (IntR), and 3.482 ± 0.069 mL/hr/kg and 12.354 ± 1.489 L for F26 (SR). The terminal phase noncompartmental rate constant (λz) of reference brand was 0.304 ± 0.026 hr-1 while its value was 0.299 ± 0.003 hr-1, 0.210 ± 0.002 hr-1, 0.052 ± 0.008 hr-1 for IR (F8), IntR (F17) and SR (F26) correspondingly. Absorption rate constant (Ka) and overall distribution rate constant (α) of reference brand was 2.079 ± 0.245 hr-1 and 1.770 ± 0.130 hr-1 while their values were 2.068 ± 0.166 hr-1, and 1.837 ± 0.133 hr-1 for IR, 0.929 ± 0.133 hr-1 and 0.924 ± 0.126 hr-1 for IntR and 0.470 ± 0.078 hr-1 and 0.550 ± 0.175 hr-1 for SR. Mean value of deposition rate constant (β) of reference formulation was 0.186 ± 0.013 hr-1, while 0.189 ± 0.019 hr-1, 0.095 ± 0.013 hr-1 and 0.051 ± 0.007 hr-1 for immediate (F8), intermediate (F17) and slow release formulations (F26) respectively. With 90% of confidence interval the bioequivalence results showed 0.991 to 0.997 for Tmaxcal, 1.003 for Cmaxcal, and 0.982 to 1.009 for AUCtotal. These results were within the acceptable limit of 0.85 to 1.25 according to FDA recommendations. The IVIVC level A correlation was explored by subjecting the in vivo data of reference, immediate (F8), intermediate (F17) and slow release formulations (F26) to software Phoenix WinNonlin® 6.2, IVIVC Tool Kit (version 2.0). Deconvolution technique with numeric approach was executed to build correlation between in vitro and in vivo drug release. The IVIVC model was validated by calculating average and individual internal predication error for Cmax and AUC last and was found to be less than 10% and 15% respectively. Best internal prediction value was obtained in phosphate buffer pH 6.8 with dissolution apparatus I (100 rpm). The values were 4.377% and 2.689 % respectively for AUClast and Cmax. External prediction error was not warranted because individual internal prediction error was not more than 15%. Point to point correlation between fraction drug dissolved and fraction drug absorbed were also estimated and the average r2 was observed as 0.986 in phosphate buffer of pH 6.8. IVIVC is now becomes a very important tool for product development of new as well as existing drug candidates. Regulatory authorities are focusing to IVIVC for product optimization since it reduces the bioequivalence burden and provide a surrogate for in vivo studies and support the biowaivers as well. Additionally through different IVIVC studies, researchers have used various dissolution conditions and variety of media to maximize drug release. Overall reduction in cost has also been reported with IVIVC. In developing countries where cost plays a critical role in quality continuance such studies will be beneficial for production of pharmaceuticals with standard quality attributes and controlled cost. The present study will provide new prospects for the formulation development and optimization with biowaiver and BCS application correlating in vitro in vivo parameters for aceclofenac tablets." xml:lang="en_US