Article

Improvement of Dissolution and Hypoglycemic Efficacy of Glimepiride by Different Carriers

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Abstract

Effects of tromethamine (Tris), polyvinylpyrrolidone (PVP-K25), and low molecular weight chitosan (LM-CH) on dissolution and therapeutic efficacy of glimepiride (Gmp) were investigated using physical mixtures (PMs), coground mixtures, coprecipitates (Coppts) or kneaded mixtures (KMs), and compared with drug alone. Fourier transform infrared spectroscopy, differential scanning colorimetry, and X-ray diffractometry were performed to identify any physicochemical interaction with Gmp. Surface morphology was examined via scanning electron microscopy. The results of Gmp in vitro dissolution revealed that it was greatly enhanced by Coppt with Tris or PVP-K25 and KM with LM-CH at a drug to carrier ratio of 1:8. Gmp amorphization by PVP-K25 and LM-CH was a major factor in increasing Gmp dissolution. Being basic, Tris might increase the pH of the microdiffusion layer around Gmp particles improving its dissolution. Formation of water-soluble complexes suggested by solubility study may also explain the enhanced dissolution. Capsules were prepared from Coppts and KM 1:8 drug to carrier binary systems and also with Tris PMs. In vivo, the hypoglycemic efficacy of Gmp capsules in rabbits increased by 1.63-, 1.50-, and 1.46-fold for 1:8 Coppts with Tris or PVP-K25 and KM with LM-CH respectively, compared with Gmp alone. Surprisingly, the response to Tris PM 1:20 capsules was 1.52-fold revealing statistically insignificant difference to that of Tris Coppt 1:8 (1.63 fold). As a conclusion, dissolution enhancement and hypoglycemic potentiation by 1:20 PM of Gmp/Tris, being simple and easy to prepare, may enable development of a reduced-dose and fast-release oral dosage form of Gmp.

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... Dissolution efficiency (DE) was calculated as percentage of the area under the dissolution curve to time t to that of the rectangle representing 100% dissolution at the same time. 37,38 Relative dissolution rate (RDR) was estimated as percentage dissolved Dcn from each binary system either SNEDDS or PM to that of the drug alone at the same time. 38,39 Kinetic modeling of dissolution data ...
... 37,38 Relative dissolution rate (RDR) was estimated as percentage dissolved Dcn from each binary system either SNEDDS or PM to that of the drug alone at the same time. 38,39 Kinetic modeling of dissolution data ...
... An amorphous drug is expected to dissolve at a faster rate than a crystalline form, due to its high energy. 38,39 With regard to carrier concentration, the effects of the carriers differed. Generally, an increase in Glc concentration from drug:carrier weight ratio 1:1 to 1:10 significantly (P,0.05) ...
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... The thermogram of unprocessed Glmp shows a sharp endothermic peak at 212.5°C, corresponding to its melting point. [17] The DSC curves of the prepared formulations showed both the absence of peaks that correspond to either the pure drug or the coformers and significant changes in enthalpy suggesting the cocrystals formation. [18,19] All the prepared formulations, except F2 and F6, exhibited lower melting temperature (T m ) than both Glmp and the coformer. ...
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... However, its low water solubility and dissolution rate cause slow onset of action and variable bioavailability and unpredictable drug plasma levels following oral administration, which can lead to the absence of therapeutic response and expose the patient to serious hyperglycemia [17]. Numerous different approaches have been applied to improve the dissolution rate and bioavailability of glimepiride, including the use of co-solvents [18], selfemulsifying drug delivery systems [19], complexation with cyclodextrins or hydrotropic agents [17], micronization [20], solid dispersions with different hydrophilic polymers [20][21][22][23], and microencapsulation by spray congealing technology using hydrophilic meltable carriers [24]. ...
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... Our results showed that GLI diffused out more rapidly from MCM-41 allowing faster release, probably because of the lack of hollow core in the structure of the particles and lower crystallinity of the drug. The former is in agreement with a recent study, where amorphization of glimepiride incorporated in solid dispersions led to faster dissolution compared to crystalline drug [36]. In our study, the dissolution rate of glimepiride loaded into both types of mesoporous systems was improved and the improvement might be attributed to partial amorphization of GLI. ...
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In this study, a significant effect of chitosan increasing nifedipine dissolution has been demonstrated. This effect was dependent on the polymer:drug mixing weight ratio, the chitosan type and the method used to disperse the drug within the polymer. The greater the chitosan content the higher the drug dissolution was, up to a maximum corresponding to a polymer:drug ratio of 3:1. Significant differences within the various tested chitosans were observed. The lower the Mw the more important the polymer effect was which, in turn, was more noticeable for the glutamate salt than for the chitosan base. The various chitosan:nifedipine solid mixtures were ordered, according to the efficiency of improving the drug dissolution, as follows: solid dispersion>kneaded mixture>co-ground mixture>physical mixture. The drug dissolution enhancement was attributed to the decreased drug crystallinity and size and polymer wetting effect. Co-grinding of chitosan along with nifedipine in a 3:1 ratio, which leads to solid mixtures exhibiting a significantly improved dissolution profile without requiring the addition of organic solvents or high temperatures for its preparation, appears to be the more simple and convenient method.
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Drug-free microparticles were prepared using a spray congealing process with the intention of studying the influence of processing parameters. By varying the atomizing pressure and liquid feed rate, microparticles with median sizes (d((0.5))) from 58 to 278 microm were produced, with total process yields ranging from 81% to 96%. An increased liquid feed rate was found to increase microparticle size, and higher atomizing pressures were found to decrease microparticle size. Greater change in microparticle size was achieved by varying atomizing pressure, which can be considered a dominant process parameter regarding microparticle size. In addition, microparticles with glimepiride, a model poorly water-soluble drug, were prepared by spray congealing using three different hydrophilic meltable carriers: Gelucire 50/13, poloxamer 188, and PEG 6000. Spherical microparticles with relatively smooth surfaces were obtained, with no drug crystals evident on the surfaces of drug-loaded microparticles. XRPD showed no change in crystallinity of the drug due to the technological process of microparticle production. All glimepiride-loaded microparticles showed enhanced solubility compared to pure drug; however, Gelucire 50/13 as a carrier represents the most promising approach to the dissolution rate enhancement of glimepiride. The influence of storage (30 degrees C/65% RH for 30 days) on the morphology of glimepiride/Gelucire 50/13 microparticles was studied, and the formation of leaf-like structures was observed (a "blooming" effect).
Article
Glimepiride (Hoe 490) is a new sulfonylurea. After oral administration of Hoe 490 to rabbits, blood glucose was lowered 3.5 times more than after glibenclamide (HB 419) and after intravenous administration, 2.5 times more. This superiority in efficacy was demonstrated by onset, maximum and duration of action. In rats, intravenous and oral Hoe 490 has a much shorter effect on blood glucose than HB 419, but the initial effect of Hoe 490 orally was up to 6 times and i.v. up to 2 times stronger than that of HB 419. In dogs, oral and intravenous Hoe 490 had a considerably longer blood glucose-lowering effect than HB 419. However, the effect of intravenous Hoe 490 was only half as intense as that of HB 419 in the first hours after treatment and the effect of oral Hoe 490 was initially stronger and thereafter temporarily distinctly weaker than that of HB 419. The more rapid decrease in blood glucose in the dog after oral administration of Hoe 490 was accompanied by a correspondingly earlier and higher plasma insulin increase. In accordance with the less intense initial blood glucose decrease in the dog after intravenous Hoe 490 there was a weaker and slower rise and faster drop of plasma insulin. The long action of oral and intravenous Hoe 490 in the dog can, however, not be sufficiently explained by the plasma insulin values. In the isolated rat pancreas perfused with glucose-free medium, HB 419 released glucagon beside insulin and somatostatin. The threshold concentration for the glucagon secretion was lower as those for the insulin and somatostatin release.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The long-term hypoglycemic activity of sulphonylurea drugs has been attributed, in part at least, to the stimulation of glucose utilization in extra-pancreatic tissues. The novel sulphonylurea, glimepiride, gives rise to a longer lasting reduction in the blood sugar level in dogs and rabbits compared to glibenclamide (Geisen K, Drug Res 38: 1120-1130, 1988). This cannot be explained adequately by elevated plasma insulin levels. This study investigated whether this prolonged hypoglycemic phase was based on the drug's abilities to stimulate glucose utilization and affect the underlying regulatory mechanisms in insulin-sensitive cells in vitro. It was found that in the absence of added insulin, glimepiride and glibenclamide (1-50 microM) stimulated lipogenesis (3T3 adipocytes) and glycogenesis (isolated rat diaphragm) approximately 4.5- and 2.5-fold, respectively, and reduced the isoproterenol-stimulated lipolysis (rat adipocytes) up to 40-60%. The increased glucose utilization was correlated with a 3-4-fold higher 2-deoxyglucose transport rate and amount of GLUT4 at the plasma membrane, as well as with increased activities of key metabolic enzymes (glycerol-3-phosphate acyltransferase, glycogen synthase) within the same concentration range. Furthermore, the low Km cAMP-specific phosphodiesterase was activated 1.8-fold, whereas the cytosolic cAMP level and protein kinase A activity ratios were significantly lowered after incubation of isoproterenol-stimulated rat adipocytes with the sulphonylureas. In many of the aspects studied the novel sulphonylurea, glimepride, exhibited slightly lower ED50-values than glibenclamide. This study demonstrates correlations existing between drug-induced stimulation of glucose transport/metabolism and cAMP degradation/protein kinase A inhibition as well as between the relative efficiencies of glimepiride and glibenclamide in inducing these extra-pancreatic processes. Therefore, it is suggested that the stimulation of glucose utilization by sulphonylureas is mediated by a decrease of cAMP-dependent phosphorylation of GLUT4 and glucose metabolizing enzymes. The therapeutic relevance of extra-pancreatic effects of sulphonylureas, in general, and of the differences between glimepiride and glibenclamide as observed in vitro in this work, in particular, remain to be elucidated.
Article
Non drug loaded lipid vesicles have been investigated as promoters of pulmonary insulin absorption. Physical mixtures of liposomes with insulin were delivered intratracheally to rats by direct instillation method at an insulin dose level of 1 U/kg. The overall hypoglycemic response, represented by area above the curve (AAC), correlated linearly with the lipid concentration for both the neutral and charged liposome-insulin preparations. The strongest response was observed with the positively charged liposomes followed by negatively charged and neutral liposome-insulin mixtures. Further toxicological studies indicated that charge-inducing agents, i.e., stearylamine and dicetylphosphate, can cause apparent disruption of pulmonary epithelial cells. From the difference of overall hypoglycemic response (AAC) among various formulations, it appears that the stronger hypoglycemic effect following positively charged liposome-insulin mixture is due to the membrane destabilizing effect on stearylamine. Optimum hypoglycemic effect was observed with a medium acyl-chain lipid (C10). The cumulative hypoglycemic response appeared to correlate inversely with the acyl carbon number of the phospholipid component from C10 to C18. The overall hypoglycemic effect does not appear to change within the liposomal size range of 0.1 micron - 1.98 microns, indicating that insulin absorption following intratracheal instillation is independent of the vesicle size within the range studied. Phospholipid promoted insulin pulmonary absorption is significantly dependent on the concentration, charge and acyl chain length of the phospholipids.
Article
To study the molecular structure of indomethacin-PVP amorphous solid dispersions and identify any specific interactions between the components using vibrational spectroscopy. Solid dispersions of PVP and indomethacin were prepared using a solvent evaporation technique and IR and FT-Raman spectra were obtained. A comparison of the carbonyl stretching region of gamma indomethacin, known to form carboxylic acid dimers, with that of amorphous indomethacin indicated that the amorphous phase exists predominantly as dimers. The hydrogen bonding of alpha indomethacin is not as dimers. Addition of PVP to amorphous indomethacin increased the intensity of the infrared band assigned to non-hydrogen bonded carbonyl. Concomitantly, the PVP carbonyl stretch appeared at a lower wavenumber indicating hydrogen bonding. Model solvent systems aided spectral interpretation. The magnitude of the spectral changes were comparable for an indomethacin-PVP solid dispersion and a solution of indomethacin in methylpyrrolidone at the same weight percent. Indomethacin interacts with PVP in solid dispersions through hydrogen bonds formed between the drug hydroxyl and polymer carbonyl resulting in disruption of indomethacin dimers. PVP may influence the crystallisation kinetics by preventing the self association of indomethacin molecules. The similarity of results for solid dispersions and solutions emphasises the "solution" nature of this binary amorphous state.
Article
We have studied the effects of chronic treatment with cromakalim (75 ug kg(-1) per day) and glibenclamide (20 mg kg(-1) per day) in alloxan-induced diabetic rats. Injection of alloxan (60 mg kg(-1)/i.v., single dose) produced a significant increase in the blood pressure, bradycardia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypothyroidism and depression in left ventricular developed pressure (LVDP). While glibenclamide significantly prevented alloxan-induced hyperglycemia and hypoinsulinaemia, it failed to alter hypertension, bradycardia, hypertriglyceridaemia and hypercholesterolemia. Treatment with cromakalim-prevented hypertension and bradycardia, but not the hyperglycemia or hypoinsulinaemia. Co-administration of cromakalim with glibenclamide antagonized the effect of glibenclamide on these parameters. Cromakalim treatment also prevented alloxan-induced hypercholesterolemia and hypertriglyceridaemia. It also produced a significant increase in serum T(3) and T(4) levels. Glibenclamide did not significantly alter alloxan-induced hypothyroidism. In conclusion our data suggest that cromakalim and glibenclamide produce some metabolic effects that are either not related to K(ATP) channel modulation or may involve different sub-types of potassium channels. Further glibenclamide when combined with cromakalim may not be beneficial in a condition when diabetes mellitus and hypertension co-exits.
Article
It was shown that the aqueous solubility of acetaminophen in the presence of polyvinylpyrrolidone (PVP) increased. The solubility at 25 degrees C increased from 14.3 m mL(-1) in the absence of PVP, to 19.7 mg m(-1) in the presence of 4% w/v PVP, and to 26.7mg mL(-1) in the presence of 8% w/v PVP. Dialysis studies indicated that there is a potential of binding between PVP and acetaminophen in their aqueous solutions. Dialysis studies also revealed that the nature of interaction between PVP and acetaminophen is physical and reversible, and there was no strong binding between PVP and acetaminophen in their solutions. Infrared spectroscopy of acetaminophen/PVP solid dispersion indicated that the mechanism of interaction between PVP and acetaminophen is via hydrogen bonding. Therefore, the increase in solubility of acetaminophen in the presence of PVP is probably attributed to its ability to form a water-soluble complex with PVP.
Article
The solubilizing and amorphizing properties toward naproxen (a poorly water-soluble antiinflammatory drug) of chitosan, an emerging pharmaceutical biopolymer, have been investigated. Solid binary systems at different drug/polymer ratios have been prepared according to different techniques (mixing, cogrinding, kneading, coevaporation) using chitosan at low (CS-L(w)) and medium (CS-M(w)) molecular weight, and tested for dissolution properties. Drug-carrier interactions were investigated in both the liquid and solid state, by phase solubility analysis, differential scanning calorimetry, X-ray powder diffractometry, FT-IR spectroscopy, and scanning electron microscopy. Drug dissolution parameters improved with increasing the polymer amount in the mixture, reaching the highest values at the 1:9 (w/w) drug/polymer ratio, and CS-L(w) was more efficacious than CS-M(w). Cogrinding was the most effective technique, showing the strongest amorphizing effect toward the drug and enabling an increase of more than ten times its relative dissolution rate. Coground mixtures at 3:7 (w/w) drug/polymer ratio were able to give directly compressed tablets which maintained unchanged the improved drug dissolution properties. Enhancer dissolution properties combined with its direct compression feasibility and antiulcerogenic action make CS-L(w) an optimal carrier for developing fast-release oral solid dosage forms of naproxen.
Article
Sulfonylureas (SUs) have been used for many years as first-line therapy for patients with type 2 diabetes mellitus whose blood glucose levels have not been effectively controlled by diet and exercise alone. Glimepiride is a once-daily SU that was introduced in 1995. Since then, a considerable body of evidence has been amassed regarding its use in type 2 diabetes. This review provides a comprehensive summary of available data on the pharmacology, pharmacokinetics, efficacy, and safety profile of glimepiride in the treatment of type 2 diabetes. It also examines the use of glimepiride to achieve and maintain good glycemic control in patients with type 2 diabetes in current clinical practice. Relevant articles were identified through a search of MEDLINE for English-language studies published from 1990 to 2002. The search terms used were glimepiride, sulfonylureas, and type 2 diabetes mellitus. The manufacturer of glimepiride provided additional information. Glimepiride differs from other SUs in a number of respects. In clinical studies, glimepiride was generally associated with a lower risk of hypoglycemia and less weight gain than other SUs. Results of other studies suggest that glimepiride can be used in older patients and those with renal compromise. There is evidence that glimepiride preserves myocardial preconditioning, a protective mechanism that limits damage in the event of an ischemic event. Glimepiride can be used in combination with other oral antidiabetic agents or insulin to optimize glycemic control. Based on the evidence to date, glimepiride is an effective and well-tolerated once-daily antidiabetic drug and provides an important treatment option for the management of type 2 diabetes.
Article
Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.
Article
The solubilizing and absorption enhancer properties towards naproxen of chitosan and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems prepared at various drug-polymer ratios by mixing, cogrinding or kneading, were characterized by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on the drug-polymer ratio and the system preparation method. Chitosan was more effective than PVP, despite the greater amorphizing power of PVP as revealed by solid state analyses. The 3/7 (w/w) drug-carrier coground systems with chitosan and PVP were the best products enabling, respectively, an improvement of 4.8 and 3.6 times of drug dissolution efficiency. In vivo experiments in mice demonstrated that administration of 45 mg/kg of drug coground with PVP or chitosan resulted, respectively, in a 25 and 60% reduction of acetic acid-induced writhings in comparison to pure drug, which, instead, was statistically ineffective as compared to the control group. Moreover, the 3/7 (w/w) drug-chitosan coground product demonstrated an antiwrithing potency 2.4 times higher than the coground with PVP. Thus, the direct-compression properties and antiulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability towards the drug, make chitosan particularly suitable for developing a reduced-dose fast-release solid oral dosage form of naproxen.
Article
We investigated the efficacy of glimepiride, a third-generation sulfonylurea (SU), in Japanese type 2 diabetic patients in whom glycemic control had been inadequate with a conventional SU, gliclazide or glibenclamide. A total of 172 Japanese type 2 diabetic patients (HbA1C > or = 7.0%), maintained on a conventional SU, were randomly assigned to the 3rd SU group (SU treatments switched to glimepiride) or the 2nd SU group (treatments not changed). The conventional SU was switched to the indicated doses of glimepiride (gliclazide 40 mg = glimepiride 1 mg, glibenclamide 2.5 mg = glimepiride 2 mg). After 6 months, glycemic control (HbA1C and fasting plasma glucose) had not changed significantly in either the 2nd or the 3rd SU group. The homeostasis assessment model of insulin resistance (HOMA-IR) in the 3rd SU group was decreased by more than 10% (p = 0.015), whereas no change was observed in the 2nd SU group. The triglyceride level was decreased by approximately 10% in the 3rd SU group, not a significant change (p = 0.080). Patients who had been treated with only SU, or treated with SU for a short time (less than 5 years), and who were also obese (BMI > or = 25) or had a high HOMA-IR (HOMA-IR > or = 3), showed significantly reduced insulin resistance. According to logistic regression analysis, high BMI ( > or = 25) was the only variable predicting that glimepiride would more effectively improve HbA1C than conventional SU treatment. In conclusion, switching conventional SUs to glimepiride reduced insulin resistance without improving glycemic control. A notable finding of this study is that glimepiride was more beneficial in obese than in non-obese Japanese type 2 diabetic patients.
Article
The effect of chitosan and of different concentrations of beta- or hydroxypropyl-beta-cyclodextrins, separately or in various (w/w) combinations, on the dissolution characteristics of glyburide (an oral hypoglycemic agent subject to incomplete and variable bioavailability) and on its permeability through Caco-2 cells has been investigated. Cyclodextrins (and particularly the hydroxypropyl-derivative, in virtue of its higher water solubility) were clearly more effective than chitosan in enhancing the drug dissolution properties: the aqueous glyburide solubility was improved 40-fold in the presence of 25 mM hydroxypropyl-beta-cyclodextrin, 25-fold in the presence of 13 mM beta-cyclodextrin (saturation solubility) and only 3-fold in the presence of chitosan at its saturation concentration (0.5% w/v). When chitosan and cyclodextrin were simultaneously present, a strong reduction of the cyclodextrin solubilizing efficiency towards the drug was observed, and it was attributed to a possible competition effect of polymer and glyburide for the interaction with the macrocycle. By contrast, permeation studies revealed that chitosan was more powerful than cyclodextrins in enhancing the glyburide permeability through Caco-2 cells. This was probably in virtue of the polymer's favourable effect on the tight junctions opening, as demonstrated by the significant decrease in the transepithelial electrical resistance recorded in its presence. Moreover, interestingly, when using the carriers together, conversely from solubility studies, a significant (P < 0.05) synergistic effect in enhancing glyburide apparent permeability was revealed in permeation experiments.
Article
Glimepiride is one of the third generation sulfonylureas used for treatment of type 2 diabetes. Poor aqueous solubility and slow dissolution rate of the drug lead to irreproducible clinical response or therapeutic failure in some cases due to subtherapeutic plasma drug levels. Consequently, the rationale of this study was to improve the biological performance of this drug through enhancing its solubility and dissolution rate. Inclusion complexes of glimepiride in beta-cyclodextrin (beta-CyD), hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) and sulfobutylether-beta-cyclodextrin (SBE-beta-CyD), with or without water soluble polymers were prepared by the kneading method. Binary systems were characterized by thermogravimetric analysis, IR spectroscopy and X-ray diffractometry. Phase solubility diagrams revealed increase in solubility of the drug upon cyclodextrin addition, showing A(p) type plot indicating high order complexation. All the ternary systems containing beta-CyD or HP-beta-CyD showed higher dissolution efficiency compared to the corresponding binary systems. The hypoglycemic effect of the most rapidly dissolving ternary system of glimepiride-HP-beta-CyD-PEG 4000 was evaluated after oral administration in diabetic rats by measuring blood glucose levels. The results indicated that this ternary system improves significantly the therapeutic efficacy of the drug. In conclusion, the association of water soluble polymers with glimepiride-CyD systems leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug.
Article
In this study the significant effect of chitosan on improving the dissolution rate and bioavailability of aceclofenac has been demonstrated by simple solvent change method. Chitosan was precipitated on aceclofenac crystals using sodium citrate as the salting out agent. The pure drug and the prepared co-crystals with different concentrations of chitosan (0.05-0.6%) were characterized in terms of solubility, drug content, particle size, thermal behaviour (differential scanning calorimetry, DSC), X-ray diffraction (XRD), morphology (scanning electron microscopy, SEM), in vitro drug release and stability studies. The in vivo performance was assessed by preclinical pharmacodynamic (analgesic and anti-inflammatory activity) and pharmacokinetic studies. The particle size of the prepared co-crystals was drastically reduced during the formulation process. The DSC showed a decrease in the melting enthalpy indicating disorder in the crystalline content. The XRD also revealed a characteristic decrease in crystallinity. The dissolution studies demonstrated a marked increase in the dissolution rate in comparison with pure drug. The considerable improvement in the dissolution rate of aceclofenac from optimized crystal formulation was attributed to the wetting effect of chitosan, decreased drug crystallinity, altered surface morphology and micronization. The optimized co-crystals exhibited excellent stability on storage at accelerated conditions. The in vivo studies revealed that the optimized crystal formulation provided a rapid pharmacological response in mice and rats besides exhibiting improved pharmacokinetic parameters in rats.
Phase-solubility techniques
  • T Higuchi
  • K A Connors
Higuchi T, Connors KA. Phase-solubility techniques. Adv Anal Chem Instr. 1965;7:117-212.