Ethiraj, T (2016) Studies on the Crystal Forms of selected Fluoroquinolones. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.
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Abstract
Prulifloxacin and Gemifloxacin are fourth generation Fluoroquinolones; they are broad-spectrum antibiotics which are active against both gram positive and gram-negative bacteria. They are mainly prescribed for the bacterial infections of complicated lower urinary tract infection, acute respiratory tract infection, simple cystitis, skin and soft tissue infection, E.N.T infection, bone and joint infection in children and adults and also community acquired pneumonia. The existence of various solid-state forms of active ingredients can drastically alter the physico-chemical properties of a pharmaceutical product. This may affect its effectiveness, stability, bioavailability, therapeutic efficacy and suitability of a particular formulation. Therefore, the development of suitable solid form is critical for the success of drug product. Solids may be prepared in a particular crystal form through various crystallization techniques. These solid forms are differing from each other with respect to many properties such as internal crystal lattice, crystal shape, solubility, dissolution rate, flow properties and compaction behavior. Particularly for drugs that are poorly water soluble, polymorphism in formulation plays a vital role since it could significantly influence the dissolution rate and solubility required to achieve adequate bioavailability. The present work was focused with the aim of preparation of various crystals of prulifloxacin and gemifloxacin mesylate using the solvents of varying polarity and by change of phase. The main objectives of this study was also achieved by conducting the experiments to characterize the newly developed crystals by Scanning Electron Microscopy, FT-IR spectroscopy, Differential Scanning Calorimetry, Powder X-ray Diffraction, in-vitro dissolution study and in-vivo pharmacokinetic study. PRULIFLOXACIN: The different crystal forms of prulifloxacin (P-I, P-II, P-III) were prepared by cooling crystallization method using acetonitrile, acetone and dichloromethane respectively. SEM photographs showed a distinct difference in the morphology of newly developed polymorphs such as plate like crystal for P-I, rod or needle shaped for P-II and prismatic for P-III which believed the formulation of different polymorphs with their corresponding crystal morphology. The FT-IR spectra of pure drug and crystalline forms of selected drug were almost identical and the main absorption bands were appeared in the entire spectrum which indicated that there was no alternation in the functional group. On the basis of FT-IR spectroscopy the crystal forms of prulifloxacin could be categorized in to three different crystal forms. From DSC analysis peak fusion point were observed at 224.01ºC, 226.44ºC , 222.33ºC and 224.91 ºC for pure form, P-I, P-II and P-III. The DSC thermogram analysis revealed that the crystal obtained from acetonitrile showed endothermic peak at 226.43º C corresponding to its melting point indicated its more stability than others. Shift of the endothermic peak towards lower temperature in P-II indicated lower melting point, hence it may be the formation of meta stable polymorph. Powder X-ray diffraction pattern of all crystal forms showed that P-I and P-II were not identical with any of the other spectra indicating that they are two different polymorphs. PXRD spectra of P-III have similar intense peaks as that of pure form. From the results of above study, three different categories of polymorphs were identified. Solubility of all the crystals was determined by determining the concentration of the drug after exposing the crystals to phosphate buffer for 24 hours. The maximum solubility was found for P-II form while the others have least solubility. P-II form showed highest percentage drug release in its dissolution profile when compared to pure form and other crystals. Finally it can be concluded that the three different polymorphs of prulifloxacin were identified based on SEM, FT-IR, DSC and PXRD studies. These polymorphs have shown difference in their solubility and dissolution profiles. Samples stored at accelerated stability condition had shown no significant changes in their drug content, demonstrating their good stability. The result of dissolution study of P-II crystal form showed impact on the pharmacokinetic studies after oral administration to Sparque-Dawley rat. The highest Cmax (1.88 μg/ml) and high area under the curve vale (AUC∞ 14.70 μg/ml) supported the better oral absorption and greater bioavailability of P-II crystal form of prulifloxacin than the pure drug. Hence, the above process increased the confident to develop the further formulation. GEMIFLOXACIN MESYLATE: The crystal forms of gemifloxacin mesylate were prepared by solvent evaporation method using isopropanol, chloroform, dichloromethane and benzene to get the fine crystals of G-I, G-II, G-III and G-IV form respectively. The SEM images of developed crystals showed different shapes and sizes due to the nature of various solvents used in their preparation. Thick rod shaped for G-I, rectangular for G-II, plate like for G-III and bricks shape for G-IV demonstrated the formation of different crystals. FT-IR spectroscopy of prepared crystal had not shown any major alternation in comparison with pure form which indicated that these crystal forms were different in their crystal habbit, but identical chemically. From the FT-IR spectrum of crystals of gemifloxacin mesylate could be categorized in to four crystal forms. DSC thermograms of the above crystalline form showed changes in melting point due to alternation in the internal molecular arrangement and other intermolecular interaction. From DSC analysis peak fusion points were observed at 206.6 ºC, 208.2 ºC, 209.8 ºC, 214.2 ºC for G-I to G-IV respectively. Lowest melting point of G-I described that it may be meta stable polymorph. The differences in the line intensities of few peaks on the XRPD spectrum of prepared crystal forms and pure form indicated the existence of different forms of crystal. Powder X-ray diffraction of all crystal forms shown spectacular results. Comparison of the spectra shown that G-I, G-II, G-III and G-IV have distinct crystal structure. From the results, all prepared crystal forms were identified as four different polymorphs. The observation from the dissolution rate profiles and solubility measurement of all the four crystalline forms explained that the G-I crystal had highest solubility and percentage drug release. Maximum solubility was found in G-I. Rest of the other crystal forms offered more or less the same solubility. The drug content observed for all the developed crystals between 97% - 98% indicated good stability after storage at accelerated stability condition. Finally it can be concluded that the four different polymorphs of gemifloxacin mesylate were identified based on SEM, FT-IR, DSC and PXRD studies. The mean peak plasma concentration of G-I form (Cmax 3.06 μg/ml) was more than the pure form which was indicative of the rate and extent of oral absorption. The absorption rate of G-I forms showed greatly up at 1 hr with highest AUC∞ value (11.88μg/ml) which expressed the higher bioavailability than pure form. This improved pharmacological response provided the potential to develop the newer dosage form of gemifloxacin mesylate in future.
| Item Type: | Thesis (Doctoral) |
|---|---|
| Uncontrolled Keywords: | Prulifloxacin, Gemifloxacin Mesylate, Crystal Forms, Fluoroquinolones. |
| Subjects: | PHARMACY > Pharmaceutics |
| Depositing User: | Subramani R |
| Date Deposited: | 20 Aug 2017 06:56 |
| Last Modified: | 27 Oct 2022 14:59 |
| URI: | http://repository-tnmgrmu.ac.in/id/eprint/2732 |
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