Intrinsic Dissolution Studies Research Articles

Diversity of Solid Forms Promoted by Ball Milling: Characterization and Intrinsic Dissolution Studies of Pioglitazone Hydrochloride and Fluvastatin Sodium Drug-Drug Systems.

Coamorphous salt in a 1:1 ratio prepared by ball milling from Fluvastatin sodium (FLV) and Pioglitazone hydrochloride (PGZ·HCl) can be selectively formed by neat grinding (NG). Furthermore, the salt-cocrystal continuum was preferably formed by employing liquid-assisted grinding (LAG) using ethanol (EtOH). Attempts to prepare the coamorphous salt starting from the salt-cocrystal continuum by NG were unsuccessful. Interestingly, through ball milling by NG or LAG, a great diversity of solid forms (PGZ·HCl-FLV 1:1) could be accessed: NG and hexane (coamorphous); ethyl acetate (physical mixture); EtOH (salt-cocrystal continuum); and water (which presents two Tg, indicating immiscibility of the components). An exploration was performed at different drug-to-drug ratios by NG. By differential scanning calorimetry (DSC), the presence of two endothermic events was observed in this screening: incongruous melting point (solidus) and excess of one of the components (liquidus), except in the 1:1 solid form. From these results, eutectic behavior was observed. Through the construction of a binary phase diagram, it was determined that the 1:1 molar ratio gives rise to the formation of the most stable coamorphous composition. Dissolution profile studies of these solid forms were carried out, specifically on pure FLV and the solid forms of PGZ⋅HCl-FLV (1:2; 1:4; and 1:6), together with the coamorphous 1:1 salt. By itself, pure FLV presented the highest Kint (13.6270 ± 0.8127 mg/cm2⋅min). On the other hand, the coamorphous 1:1 showed a very low Kint (0.0220 ± 0.0014 mg/cm2·min), indicating very fast recrystallization by the FLV, which avoids observing a sudden release of this drug in the solution. This same behavior was observed in the eutectic composition 1:2. In the other solid forms, the value of Kint increases along with the %w of FLV. From the mechanochemical point of view, ball milling by NG or LAG became an important synthetic tool since it allows obtaining a great variety of solid forms to explore the solid-state reactivity of the drug-drug solid-form PGZ HCl-FLV.

Prediction of food effect on in vitro drug dissolution into biorelevant media: Contributions of solubility enhancement and relatively low colloid diffusivity

A prior model that showed good predictability for fed-state and fasted-state biorelevant media was extended to predict the degree to which fed-state biorelevant media (i.e. FeSSGF and FeSSIF-V2) enhanced drug dissolution over fasted-state biorelevant media (i.e. FaSSGF and FaSSIF-V2): ϕfood=vfast1/6vfed1/6·(ff,fedDD2/3+fm,fedDD−M,fed2/3)[Dt,fed](ff,fastDD2/3+fm,fastDD−M,fast2/3)[Dt,fast] where ϕfood is the degree by which fed-state biorelevant media enhanced in vitro drug dissolution over fasted state biorelevant media, ff,fast and ff,fed are the fraction of free drug in fasted and fed biorelevant media, fm,fast and fm,fed are the fraction of drug in fasted and fed mixed micelles (or fat globules in FeSSGF), DD is the free drug diffusivity, DD−M, fast and DD−M, fed are the fasted and fed mixed micelle (or fat globule) diffusivity, and [Dt,fast] and [Dt,fed] are the total drug solubilities in fasted and fed-state biorelevant media, respectively. Solubility, particle size measurement, and intrinsic dissolution studies were performed for model BCS Class II drugs griseofulvin, ketoconazole, and ibuprofen each in FaSSGF, FeSSGF, FaSSIF-V2, and FeSSIF-V2 to compare observed versus predicted dissolution enhancement in fed-state over fasted-state biorelevant media. Relative to solubilization, in vitro dissolution was many fold lower in fed media over fasted media, indicating the compromising role of micellar and fat-globule diffusivity in attenuating dissolution rate based on solubility enhancement alone. Results of ϕfood agreed with what was observed and were also corroborated by reported food effects in vivo for griseofulvin, ketoconazole, and ibuprofen. The understanding of attenuation of in vitro dissolution in fed versus fasted biorelevant media may contribute towards predicting in vivo food effects, including lack of in vivo food effect for some poorly water soluble drugs.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

Preparation, characterization, intrinsic dissolution studies and microbiological assessment of dapsone tosylate polymorphs

Purpose: To prepare dapsone tosylate salt (TD) and its two polymorphs (TD-I and TD-II), and study their intrinsic dissolution profiles and preliminary anti-mycobacterium activity. Methods: The synthesized product was studied with respect to the effect of solvent selection, reaction temperature and evaporation rate on the solid phase obtained. The polymorphs were characterized using powder x-ray diffraction (PXRD), proton nuclear magnetic resonance ( 1 H-NMR), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). UV/Vis spectroscopy was employed for quantification of the salt, while Wood apparatus was used for dissolution studies. Microdilution assay, using a 96-well equipment, was employed for the evaluation of anti-mycobacterial activity. Results: On analysis of the solids obtained from synthesis with PXRD, two different patterns were observed. One pattern belonged to TD-I, previously reported, and the other was a new polymorph TD-II. Solvent evaporation was important in the selective preparation of TD-I or TD-II. Analyses with DSC, TGA and 1 H-NMR revealed the absence of solvent in both solids and showed that TD-II was not a solvated salt. Spectral analysis with FT-IR demonstrated structural relationship between TD-I and TD-II. Intrinsic dissolution studies showed that both polymorphs dissolved faster than dapsone (DAP). Conclusion: It is possible to synthesize TD and select the polymorph prepared by means of modulated solvent evaporation rate. The rank order of the intrinsic dissolution rate constants was TD-II > TD-I > DAP. The tosylate salt enhanced inhibitory effect on M. fortuitum, when compared to DAP. Keywords: Dapsone tosylate, Polymorphism, Solid phase characteristics, Intrinsic dissolution, Antimycobacterium activity

Preparation and characterization of pyrimethamine solid dispersions and an evaluation of the physical nature of pyrimethamine in solid dispersions

The objective of this investigation was to prepare, characterize pyrimethamine solid dispersions formulated with different carriers and to evaluate the physical nature of pyrimethamine in solid dispersion. Pyrimethamine solid dispersions were prepared by solvent evaporation technique using a rotary evaporator and characterized using intrinsic dissolution studies, differential scanning calorimetry (DSC), x-ray diffractometry (XRD), fourier transform infrared spectroscopy (FTIR), dissolution studies, and stability studies of selected solid dispersion. To further investigate the nature of drug, nuclear magnetic resonance was also performed. Intrinsic dissolution studies demonstrate that the dissolution rate of pyrimethamine could be markedly improved via solid dispersion technique. DSC studies show that PEG 6000 and poloxamer 188 could dissolve pyrimethamine up to 50% (w/w) in molten state. Results of XRD and FTIR suggest the presence of a different polymorphic form of pyrimethamine which might be due to the disruption of the supramolecular ribbon (synthon) formation of the original pyrimethamine polymorph. Significant improvement in dissolution rate from pyrimethamine solid dispersion using poloxamer 188 was achieved and pyrimethamine/poloxamer 188 ratio at 1:3 showing maximum dissolution rate enhancement of pyrimethamine. Furthermore, stability studies indicate no significant change in the physical nature of pyrimethamine in selected solid dispersion up to 5-month.

Oral bioavailability enhancement of β-lapachone, a poorly soluble fast crystallizer, by cocrystal, amorphous solid dispersion, and crystalline solid dispersion

The aim of this paper was to compare the in vitro dissolution and in vivo bioavailability of three solubility enhancement technologies for β-lapachone (LPC), a poorly water soluble compound with extremely high crystallization propensity. LPC cocrystal was prepared by co-grinding LPC with resorcinol. LPC crystalline and amorphous solid dispersions (CSD and ASD) were obtained by spray drying with Poloxamer 188 and HPMC-AS, respectively. The cocrystal structure was solved by single crystal x-ray diffraction. All formulations were characterized by WAXRD, DSC, POM and SEM. USP II and intrinsic dissolution studies were used to compare the in vitro dissolution of these formulations, and a crossover dog pharmacokinetic study was used to compare their in vivo bioavailability. An 1:1 LPC-resorcinol cocrystal with higher solubility and faster dissolution rate was obtained, yet it converted to LPC crystal rapidly in solution. LPC/HPMC-AS ASD was confirmed to be amorphous and uniform, while the crystal and crystallite sizes of LPC in CSD were found to be ∼1–3 μm and around 40 nm, respectively. These formulations performed similarly during USP II dissolution, while demonstrated dramatically different oral bioavailability of ∼32%, ∼5%, and ∼1% in dogs, for CSD, co-crystal, and ASD, respectively. CSD showed the fastest intrinsic dissolution rate among the three. The three formulations showed poor IVIVC which could be due to rapid and unpredictable crystallization kinetics. Considering all the reasons, we conclude that for molecules with extremely high crystallization tendency that cannot be inhibited by any pharmaceutical excipients, size-reduction technologies such as CSD could be advantageous for oral bioavailability enhancement in vivo than technologies only generating transient but not sustained supersaturation.

Performance comparison between crystalline and co-amorphous salts of indomethacin-lysine

The introduction of a highly water soluble amino acid as co-amorphous co-former has previously been shown to significantly improve the dissolution rate of poorly water soluble drugs. In this work, dry ball milling (DBM) and liquid assisted grinding (LAG) were used to prepare different physical forms of salts of indomethacin (IND) with the amino acid lysine (LYS), allowing the direct comparison of their solid-state properties to their in vitro performance. X-ray powder diffraction and Fourier-transformed infrared spectroscopy showed that DBM experiments led to the formation of a fully co-amorphous salt, while LAG resulted in a crystalline salt. Differential scanning calorimetry showed that the samples prepared by DBM had a single glass transition temperature (Tg) of approx. 100°C for the co-amorphous salt, while a new melting point (223°C) was obtained for the crystalline salt prepared by LAG. Intrinsic dissolution and powder dissolution studies demonstrated an increased dissolution rate of the drug in the co-amorphous salt compared to pure amorphous IND and also the crystalline drug-LYS salt. Furthermore, the co-amorphous IND-LYS salt presented long term physical stability in dry conditions at 25°C and 40°C. Overall, it has been shown that the co-amorphous form of a salt has a superior performance in comparison to a crystalline salt.

Multicomponent solid forms of felodipine: preparation, characterisation, physicochemical and in-vivo studies.

This study aimed to improve biopharmaceutical parameters of the poorly soluble antihypertensive drug, felodipine, by preparing multicomponent solid forms using three coformers, viz. imidazole, nicotinamide and malonic acid. The multicomponent solid forms were prepared by mechanochemical synthesis and characterised by various analytical techniques. These solid forms were further assessed for their physicochemical parameters. Pharmacokinetic and in-vivo antihypertensive activity was performed in rats. Felodipine (FEL) was found to be cocrystallised with imidazole (FEL-IM) while it formed eutectic with nicotinamide (FEL-NCT) and malonic acid (FEL-MA). Cocrystal was sustained by NH…N and NH….O hydrogen-bonded network. Solubility and intrinsic dissolution studies in 0.1 N HCl (pH 1.2) revealed that eutectics exhibited higher solubility and release rate than cocrystal vis-a-vis pure drug and were found to be stable under accelerated storage condition. Significant enhancement of bioavailability was observed in eutectics (3.5- to twofold) and cocrystal (1.3-fold) compared with the pure drug. Antihypertensive activity of new solid forms in an animal model showed a marked decrease in systolic blood pressure. Mechanochemical approach was successful to prepare multicomponent solid forms that have the potential to improve biopharmaceutical parameters of the poorly soluble drug, FEL.

Characterisation, solubility and intrinsic dissolution behaviour of benzamide: dibenzyl sulfoxide cocrystal

This study examined the 1:1 cocrystal benzamide:dibenzyl sulfoxide, comprising the poorly water soluble dibenzyl sulfoxide (DBSO) and the more soluble benzamide (BA), to establish if this cocrystal shows advantages in terms of solubility and dissolution in comparison to its pure components and to a physical mixture. Solubility studies were performed by measuring DBSO solubility as a function of BA concentration, and a ternary phase diagram was constructed. Dissolution was examined through intrinsic dissolution studies. Solid-state characterisation was carried out by powder X-ray diffraction (PXRD), energy-dispersive X-ray diffraction (EDX), infra-red spectroscopy (ATR-FTIR) and thermal analysis. DBSO solubility was increased by means of complexation with BA. For the cocrystal, the solubility of both components was decreased in comparison to pure components. The cocrystal was identified as metastable and incongruently saturating. Dissolution studies revealed that dissolution of DBSO from the cocrystal was not enhanced in comparison to the pure compound or a physical mix, while BA release was retarded and followed square root of time kinetics. At the disk surface a layer of DBSO was found. The extent of complexation in solution can change the stability of the complex substantially. Incongruent solubility and dissolution behaviour of a cocrystal can result in no enhancement in the dissolution of the less soluble component and retardation of release of the more soluble component.

Cocrystal Intrinsic Dissolution Behavior Using a Rotating Disk

The aim of this study was to investigate the dissolution characteristics of an acetaminophen/theophylline (AT) cocrystal compared with its pure components and physical mixtures. Intrinsic dissolution studies were conducted by a rotating-disk method. Solubility studies were conducted by collecting transient samples at 5, 30, and 60 min and equilibrium samples after 72 h, both at 37 °C. The AT cocrystal had a faster dissolution rate than AT physical mixtures, and the dissolution profiles were congruent (1:1 mole ratio) under different pH conditions. Thus, the AT cocrystal dissolved congruently at short times and exhibited higher transient solubility compared with its two pure components. Equilibrium solubilities of theophylline from the cocrystal were lower than transient values due to theophylline hydrate precipitation but no precipitation of free acetaminophen occurred. The solubility behavior of acetaminophen and theophylline exhibited typical 1:1 complex formation in physical mixtures, cocrystal, and phase-solubility studies. The Levich equation was used to predict the dissolution behavior of the AT cocrystal as well as that of the single components.

A Comparison of Spray Drying and Milling in the Production of Amorphous Dispersions of Sulfathiazole/Polyvinylpyrrolidone and Sulfadimidine/Polyvinylpyrrolidone

Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 ≤ X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 ≤ X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 ≤ X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (χ) were determined for the two systems (χ = -1.8 for SDM, χ = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co-milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems.

Improved Pharmacokinetics of AMG 517 Through Co-Crystallization Part 1: Comparison of Two Acids With Corresponding Amide Co-crystals

The dissolution and pharmacokinetics (PK) of two carboxylic acid co-crystals (cinnamic acid and benzoic acid) with the corresponding amide co-crystals (cinnamamide and benzamide) of AMG 517 were investigated. Powder and intrinsic dissolution studies were performed in fasted simulated intestinal fluid (FaSIF). Suspension formulations in 1% polyvinylpyrrolidone K25 in water were administered orally at 100 mg/kg to rats. The four co-crystals were found to have faster intrinsic and powder dissolution rates in FaSIF than the free base. This correlated with a 2.4- to 7.1-fold increase in the area under the concentration-time curve in rat PK investigations. When contrasting the acid to its corresponding amide co-crystal, cinnamamide shows improvement over cinnamic acid, while benzamide and benzoic acid perform similarly.

Pharmaceutical Composition of Valsartan: β-Cyclodextrin: Physico–Chemical Characterization and Anti-Hypertensive Evaluation

Valsartan, a water-insoluble drug, is mainly used in the treatment of hypertension albeit with reduced oral bioavailability. The aim of work was to develop a valsartan:β-cyclodextrin (VAL:β-CD) pharmaceutical composition in order to improve its water solubility and bioavailability. The VAL:β-CD complexes were prepared by the kneading, solid dispersion and freeze-drying methods, of which the freeze-drying method (FDY) was found to be the best to prepare an inclusion complex. A physical mixtyure PM was also prepared. Complexes were characterized by thermal analysis, Fourier transformed- infrared (FTIR) spectroscopy, Powder X-ray diffractometry, intrinsic dissolution and NMR (2D-ROESY). Phase-solubility analysis showed AL-type diagrams with β-cyclodextrin (β-CD). Microcalorimetric titrations suggested the formation of 1:1 inclusion complex between VAL and β-CD. The apparent stability constants K1:1 calculated from phase-solubility plots were 165.4 M-1 (298 K), 145.0 M-1 (303 K) and 111.3 M-1 (310 K). In vivo experiments in rats showed that reduction in arterial pressure for the FDY complex is better than with valsartan used alone. The better activity of FDY can be attributed to the higher solubility of valsartan after inclusion in the cyclodextrin cavity, as suggest by the intrinsic dissolution studies.

The influence of aggregate microenvironment on the dissolution of oxazepam in ternary surfactant interactive mixtures.

The purpose of this research was to test the hypothesis that the dissolution rate of oxazepam in interactive mixtures was dependent on the influence of surfactant within the microenvironment of mixed oxazepam-surfactant aggegrates produced during dissolution. The studies utilised both powder and intrinsic dissolution methodology; spectrophotometric assays were developed and validated and dissolution data were modelled using multi-exponential equations and dissolution rate constants estimated using non-linear least squares algorithms. For a series of water-soluble ternary additives to the oxazepam interactive mixture, sodium lauryl sulfate and cetrimide were shown not only to decrease aggregation through enhanced dispersion, but also to increase the dissolution rate constant. Such an increase in dissolution rate constant was observed in the intrinsic dissolution studies when surfactant concentrations exceeded the critical micelle concentration and the oxazepam solubility increased. Laser diffraction particle sizing during the dissolution process confirmed the presence of dispersed particles and aggregates and demonstrated that the presence of surfactant improved the state of dispersion. The results of studies using different rotational speeds produced unexpected increases in aggregation and decreases in dissolution rate constants at about 150 rev min(-1), consistent with the transient formation of loose aggregates containing dissolved surfactant.

Effect of Polymer Additives on the Transformation of BMS-566394 Anhydrate to the Dihydrate Form

To investigate the effect of polymer additives on the transformation of BMS-566394 anhydrate to the dihydrate form and to propose the possible mechanisms for inhibition of conversion of the anhydrate to the dihydrate form. The conversion of anhydrate to dihydrate was monitored using differential scanning calorimetry, powder X-ray diffraction and polarized light microscopy. Solubility and intrinsic dissolution studies were performed on anhydrate and dihydrate. IR and NMR spectroscopy were used to probe the molecular interactions between BMS-566394 and cellulose ether polymers. The anhydrate form of BMS-566394 was readily transformed into the more stable dihydrate form in aqueous suspension. The kinetic solubility and intrinsic dissolution rate of the anhydrate were ca. fourfold that of the dihydrate. Addition of cellulose ether polymers (HPC, HPMC, MC) inhibited anhydrate to dihydrate transformation in aqueous suspensions. Hydrogen bonding interaction between the polar groups of the drug and polymers was inferred from infrared spectroscopy. Solution NMR also indicated a hydrophobic interaction between the drug and polymer backbone. The anhydrate form of BMS-566394 is stabilized in the presence of cellulose ether polymers. Spectroscopic evidence is offered to postulate a molecular interaction between drug and polymers.

Hydrate modifications of the non-steroidal anti-inflammatory drug diclofenac sodium: Solid-state characterisation of a trihydrate form

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in painful and inflammatory diseases. It can exist in different hydrate phases. By exposure to different conditions of temperature and relative humidity can be isolated a trihydrate form never described in literature. The methods of preparation of the trihydrate form (named DSH3) were described and its physico-chemical properties were investigated. Data from FTIR spectroscopy, X-ray powder diffraction and thermal analysis were used for identification and characterisation of DSH3 in comparison with the anhydrous form (DS, the commercial form) and the hydrate form DSH (obtained by exposure of DS to relative humidity even below 60% and already described and characterised in a previous article of the same authors). Intrinsic dissolution studies were performed to compare the pharmaceutical properties of DS and DSH with DSH3, since this form was accidentally found on the Italian market as active pharmaceutical ingredient (API). This work stresses the importance of assessing the correct crystalline form also in API of well-established use to guarantee quality, safety and efficacy of the final dosage form. Furthermore, this study suggests that isomorphic hydrate forms with a different dislocation of water within the crystal structures can exist.

A critical evaluation of fasted state simulating gastric fluid (FaSSGF) that contains sodium lauryl sulfate and proposal of a modified recipe

The aim of this work is to evaluate one of the most commonly used fasted state simulating gastric fluids (FaSSGFs), which contains sodium lauryl sulfate (SLS) (FaSSGF SLS), and propose a more appropriate surfactant concentration. Surface tension studies clearly show that the critical micelle concentration (CMC) of SLS in the relevant media (a media whose pH and sodium chloride concentration are representative of physiological conditions) is significantly lower ( p < 0.05) than 8.67 mM, which is the SLS concentration in FaSSGF SLS. The CMC of SLS in the relevant media was determined to be 1.75 mM. Based on this a modified recipe is proposed in which the concentration of SLS is sufficient to achieve a surface tension similar to that in vivo without causing artificial micellar solubilization. Solubility, intrinsic dissolution, and GastroPlus™ modeling studies are presented to support and give rationale for the modified recipe. In addition, a comparison between the modified recipe and other FaSSGFs reported in the literature is made.

Does the preferred orientation of crystallites in tablets affect the intrinsic dissolution?

The aim of this study was to examine the effect of preferred orientation of crystallites, i.e. texture, on the intrinsic dissolution rate of some active pharmaceutical ingredients. Although it has often been speculated that the intrinsic dissolution of pharmaceutical tablets is affected by texture, no experimental evidence of this effect has been reported. The texture of acetylsalicylic acid, tolbutamide, carbamazepine and entacapone tablets was measured using three different methods both before and after the dissolution measurements. To clarify the effect of texture, texturizing and less-texturizing batches of each material were used. The texturizing batches had big needle or plate-like particles and the less-texturizing batches were prepared by grinding the texturizing powders. The USP rotation disc method was used to measure the intrinsic dissolution rate of the samples. The results indicated that the acetylsalicylic acid, tolbutamide and entacapone tablets texturized strongly in compression and the grinding of the texturizing powders decreased the degree of texture. Also the carbamazepine tablets were slightly texturized. All of the texture measurement methods used were found to give acceptable and consistent results and therefore a special texture goniometer is not required to perform these measurements. The intrinsic dissolution rate of all the tablets compacted from the ground powder was slightly higher than the intrinsic dissolution rate of the more texturized samples. However, these differences were not significant on a large scale. After the dissolution tests the degree of texture of the samples was decreased. The intrinsic dissolution rates of the samples were presumably affected by several different parameters such as texture, solubility, pH, surface energetics and crystal strains. Although only small differences were found between the intrinsic dissolution rates of texturized and less texturized samples the effect of texture on the dissolution behavior of the pharmaceuticals should be considered when performing accurate intrinsic dissolution studies.

Physico-chemical characterisation and intrinsic dissolution studies of a new hydrate form of diclofenac sodium: comparison with anhydrous form

Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in painful and inflammatory diseases. In standard conditions, by exposure to relative humidity even below 60% at 25 °C, the anhydrous form DS gives rise to a hydrate species DSH, a tetrahydrate form different from that obtained by crystallisation from water and previously described. The method of preparation and the physico-chemical properties of the hydrate form were investigated. Data from FTIR spectroscopy, X-ray powder diffraction and thermal analysis were used for the identification and the characterisation of DSH. DS and DSH were easily differentiated by their IR spectra, X-ray patterns and thermal behaviour. DSH stability was followed at room temperature over a period of 1 year and under different conditions of temperature to verify the tendency to solid–solid transition and to study its existence range. Solubility and intrinsic dissolution studies were performed to compare the physico-chemical properties of DS and DSH. Differences in solubility and intrinsic dissolution rates were pointed out: these studies showed that DS dissolved faster than DSH. Storage under uncontrolled environmental conditions or contact with water vapour during manufacturing process could thus influence the performance of the final dosage form.

Characterisation of salts of drug substances

The properties of the solid-state of drug substances are critical factors that determine the choice of an appropriate salt form for the development of the pharmaceutical formulation. The most relevant properties may affect the therapeutic efficacy, toxicity, bioavailability, pharmaceutical processing and stability. The salt form must fulfil the needs of the targeted formulation, be suitable for full-scale production and its solid-state properties maintained batchwise as well as over time. Comparison of the solid-state properties of different salt candidates may be quite complicated if each salt candidate exist as different solid phases: polymorphs, solvates or amorphous forms. Thermal analysis, microcalorimetry and combined techniques, X-ray diffraction, solubility, intrinsic dissolution, sorption-desorption and stability studies are basic techniques for the characterisation of the salt candidates. Some examples show the role of the salt form as well as the polymorphic form in the characteristics of the solid-state. Thermal analysis and combined techniques are efficient for the detection of unexpected phase transitions and for the comparison of the suitability of the salt candidates prepared for salt selection.