Mahmoud M. Al Omari

Novel inclusion complex of ibuprofen tromethamine with cyclodextrins: Physico-chemical characterization

Guest-host interactions of ibuprofen tromethamine salt (Ibu.T) with native and modified cyclodextrins (CyDs) have been investigated using several techniques, namely phase solubility diagrams (PSDs), proton nuclear magnetic resonance ((1)H NMR), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffractometry (XRPD), scanning-electron microscopy (SEM) and molecular mechanics (MM). From the analysis of PSD data (A(L)-type) it is concluded that the anionic tromethamine salt of ibuprofen (pK(a)=4.55) forms 1:1 soluble complexes with all CyDs investigated in buffered water at pH 7.0, while the neutral form of Ibu forms an insoluble complex with beta-CyD (B(S)-type) in buffered water at pH 2.0. Ibu.T has a lower tendency to complex with beta-CyD (K(11)=58 M(-1) at pH 7.0) compared with the neutral Ibu (K(11)=4200 M(-1)) in water. Complex formation of Ibu.T with beta-CyD (DeltaG(o)=-20.4 kJ/mol) is enthalpy driven (DeltaH(o)=-22.9 kJ/mol) and is accompanied by a small unfavorable entropy (DeltaS(o)=-8.4 J/mol K) change. (1)H NMR studies and MM computations revealed that, on complexation, the hydrophobic central benzene ring of Ibu.T and part of the isobutyl group reside within the beta-CyD cavity leaving the peripheral groups (carboxylate, tromethamine and methyl groups) located near the hydroxyl group networks at either rim of beta-CyD. PSD, (1)H NMR, DSC, FT-IR, XRPD, SEM and MM studies confirmed the formation of Ibu.T/beta-CyD inclusion complex in solution and the solid state.

Effect of cyclodextrins on the solubility and stability of candesartan cilexetil in solution and solid state

Guest-host interactions of candesartan cilexetil (CAND) with cyclodextrins (CyDs) have been investigated using phase solubility diagrams (PSD), X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC) and molecular mechanical modelling (MM). Estimates of the complex formation constant (K(11)) show that the tendency of CAND (pK(a)=6.0) to complex with CyDs follows the order: β-CyD>HP-β-CyD>γ-CyD>α-CyD. Complex formation of CAND with β-CyD (ΔG°=-31.5 kJ/mol) is largely driven by enthalpy change (ΔH°=-32.8 kJ/mol) and slightly retarded by entropy change (ΔS°=-4.6J/mol K). The HPLC results indicate that complex prepared by freeze drying method is chemically not stable due to the formation of amorphous CAND. Also it may suggest formulating CAND with β-CyD by kneading (dispersion) or co-evaporation (real inclusion complex) methods into capsule rather than compressed in tablets, where the compression enhances the instability of CAND. DSC thermograms for CAND/β-CyD complexes proved the formation of inclusion complexes with new solid phase. MM studies indicate the partial penetration of CAND into the β-CyD cavity.

Preparation and characterization of a novel co-processed excipient of chitin and crystalline mannitol.

A co-processed excipient was prepared from commercially available crystalline mannitol and α-chitin using direct compression as well as spray, wet, and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size, on the properties of the prepared co-processed excipient has been investigated. α-Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol–chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol–chitin (2:8, w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength, and friability of tablets, produced from Cop-MC using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, high-strength, and low-strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient.

Chitin and Chitosan as Direct Compression Excipients in Pharmaceutical Applications

Despite the numerous uses of chitin and chitosan as new functional materials of high potential in various fields, they are still behind several directly compressible excipients already dominating pharmaceutical applications. There are, however, new attempts to exploit chitin and chitosan in co-processing techniques that provide a product with potential to act as a direct compression (DC) excipient. This review outlines the compression properties of chitin and chitosan in the context of DC pharmaceutical applications.

Influence of Molecular Weight and Degree of Deacetylation of Low Molecular Weight Chitosan on the Bioactivity of Oral Insulin Preparations

The objective of the present study was to prepare and characterize low molecular weight chitosan (LMWC) with different molecular weight and degrees of deacetylation (DDA) and to optimize their use in oral insulin nano delivery systems. Water in oil nanosized systems containing LMWC-insulin polyelectrolyte complexes were constructed and their ability to reduce blood glucose was assessed in vivo on diabetic rats. Upon acid depolymerization and testing by viscosity method, three molecular weights of LMWC namely, 1.3, 13 and 18 kDa were obtained. As for the DDA, three LMWCs of 55%, 80% and 100% DDA were prepared and characterized by spectroscopic methods for each molecular weight. The obtained LMWCs showed different morphological and in silico patterns. Following complexation of LMWCs with insulin, different aggregation sizes were obtained. Moreover, the in vivo tested formulations showed different activities of blood glucose reduction. The highest glucose reduction was achieved with 1.3 kDa LMWC of 55% DDA. The current study emphasizes the importance of optimizing the molecular weight along with the DDA of the incorporated LMWC in oral insulin delivery preparations in order to ensure the highest performance of such delivery systems.

Fexofenadine/Cyclodextrin Inclusion Complexation: Phase Solubility, Thermodynamic, Physicochemical, and Computational Analysis

Interactions of fexofenadine (Fexo) with cyclodextrins (CDs: α- β-, γ-, and HP-β-CD) were investigated by several techniques including phase solubility, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), 1H-nuclear magnetic resonance (1H-NMR) and molecular mechanical modeling (MM+). The effects of CD type, pH, ionic strength, and temperature on complex stability were also explored. Fexo/CD complex formation follows the decreasing order: β-CD > HP-β-CD > γ-CD > α-CD (i.e., at pH 7.0 and 30°C, K11 = 1139, 406, 130, and 104 M−1, respectively). The linear correlation of the free energy of Fexo/β-CD complex formation (ΔG11) with the free energy of inherent Fexo solubility (ΔGSo), obtained from the variation of K11 with inherent Fexo solubility (So) at different pHs and ionic strengths, was used to measure the contribution of the hydrophobic character of Fexo to escape from water by including into the hydrophobic CD cavity. The hydrophobic effect (desolvation) contributes about 76% of the total driving force towards inclusion complex formation, while specific interactions contribute −7.7 kJ/mol. Moreover, Zwitterionic Fexo/β-CD complex formation appears to be driven both by favorable enthalpy (ΔH° = −23.2 kJ/mol) and entropy (ΔS° = 15.2 J/mol.K) changes at pH 7.0. 1H-NMR and MM+ studies indicate multimodal inclusion of the piperidine, carboxypropylphenyl, and phenyl moieties into the β-CD cavity. MM+ computations indicate that the dominant driving force for complexation is Van der Waals force with very little electrostatic contribution. 1H-NMR, DSC, and XRPD studies indicate the formation of inclusion complex in aqueous solution and the solid state.

Low Molecular Weight Chitosan–Insulin Polyelectrolyte Complex: Characterization and Stability Studies

The aim of the work reported herein was to investigate the effect of various low molecular weight chitosans (LMWCs) on the stability of insulin using USP HPLC methods. Insulin was found to be stable in a polyelectrolyte complex (PEC) consisting of insulin and LMWC in the presence of a Tris-buffer at pH 6.5. In the presence of LMWC, the stability of insulin increased with decreasing molecular weight of LMWC; 13 kDa LMWC was the most efficient molecular weight for enhancing the physical and chemical stability of insulin. Solubilization of insulin-LMWC polyelectrolyte complex (I-LMWC PEC) in a reverse micelle (RM) system, administered to diabetic rats, results in an oral delivery system for insulin with acceptable bioactivity.

Chapter 2 - chitin

A comprehensive profile of chitin with 61 references is reported. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for chitin and its derivative, such as chitosan, are discussed. Physical properties, analytical methods, uses and applications, stability, biodegradability, and toxicity of chitin are also reviewed.

Co-Processed Chitin-Mannitol as a New Excipient for Oro-Dispersible Tablets

This study describes the preparation, characterization and performance of a novel excipient for use in oro-dispersible tablets (ODT). The excipient (Cop–CM) consists of chitin and mannitol. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) and produced by roll compaction (RC). Differential scanning calorimetry (DSC), Fourier transform-Infrared (FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques were used to characterize Cop–CM, in addition to characterization of its powder and ODT dosage form. The effect of particle size distribution of Cop–CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a) for Cop–CM was calculated from a Kawakita plot and found to be higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin (0.818). Montelukast sodium and domperidone ODTs produced, using Cop–CM, displayed excellent physicochemical properties. The exceptional binding, fast wetting and superdisintegration properties of Cop–CM, in comparison with commercially available co-processed ODT excipients, results in a unique multifunctional base which can successfully be used in the formulation of oro-dispersible and fast immediate release tablets.

Enhancement of Thiacetazone Solubility by Isoniazid in Aqueous Solutions

AbstractThe aqueous solubility of thiacetazone was enhanced in the presence of different concentrations of isoniazid. The nature of this solubilization was investigated by measuring some physicochemical properties of isoniazid in water. Slight surface activity and conductance were observed. Osmotic pressure and partition coefficient measurements indicated that isoniazid dimerizes in aqueous solutions and were used to obtain and verify the dimerization constant. There was no evidence of higher oligomer formation in concentrations lower than 1.0 M. This excluded the possibility of solubilization by aggregate formation. Citric and glutaric acids in the presence of isoniazid were found to increase thiacetazone solubility as a function of the acid concentration and structure.