Intrinsic Dissolution Rate Measurements Research Articles

Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media.

The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.

Correction to Fast Determination of Phase Stability of Hydrates Using Intrinsic Dissolution Rate Measurements

RETURN TO ISSUEPREVAdditions and Correc...Additions and CorrectionsNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Fast Determination of Phase Stability of Hydrates Using Intrinsic Dissolution Rate MeasurementsHongliang WenHongliang WenMore by Hongliang Wen, Chenguang WangChenguang WangMore by Chenguang Wanghttp://orcid.org/0000-0003-1926-5722, and Changquan Calvin Sun*Changquan Calvin SunMore by Changquan Calvin Sunhttp://orcid.org/0000-0001-7284-5334Cite this: Cryst. Growth Des. 2019, 19, 12, 7464Publication Date (Web):November 5, 2019Publication History Published online5 November 2019Published inissue 4 December 2019https://doi.org/10.1021/acs.cgd.9b01432Copyright © 2019 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views290Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (438 KB) Get e-AlertsSUBJECTS:Solvates,Dissolution,Stability Get e-Alerts

Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs

A crystalline adduct of the anti-tubercular drug, moxifloxacin and trans-cinnamic acid (1:1 molar ratio (MCA1:1)) was prepared to prolong the residence time of the drug in the lungs by reducing its solubility and dissolution rate. Whether the adduct is a salt or cocrystal has not been unequivocally determined. Equilibrium solubility and intrinsic dissolution rate measurements for the adduct (MCA1:1) in phosphate buffered saline (PBS, pH 7.4) revealed a significant decrease in the solubility of moxifloxacin (from 17.68 ± 0.85 mg mL−1 to 6.10 ± 0.05 mg mL−1) and intrinsic dissolution rate (from 0.47 ± 0.04 mg cm−2 min−1 to 0.14 ± 0.03 mg cm−2 min−1) compared to the supplied moxifloxacin. The aerosolization behaviour of the adduct from an inhaler device, Aerolizer®, using a Next Generation Impactor showed a fine particle fraction of 30.4 ± 1.2%. The dissolution behaviour of the fine particle dose of respirable particles collected was assessed in a small volume of stationary mucus fluid using a custom-made dissolution apparatus. The respirable adduct particles showed a lower dissolution (microscopic observation) and permeation compared to the supplied moxifloxacin. The crystalline adduct MCA1:1 has a lower solubility and dissolution rate than moxifloxacin and could improve the local residence time and therapeutic action of moxifloxacin in the lungs.

Preparation, Pharmaceutical Properties and Stability of Lesinurad Co-crystals and Solvate

Lesinurad is a BCS class 2, low solubility drug, indicated for hyperglycemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. Co-crystallization and solvate formation with pharmaceutically acceptable coformers and solvents are one of the best ways to improve solubility of BCS class 2 drugs. Lesinurad DMSO (dimethyl sulphoxide) solvate (1:1 mole ratio), urea and 4-Hydroxy benzoic acid co-crystals (1:1 mole ratio) prepared and scaled up to 100g and characterized using PXRD, FTIR, DSC, TGA, solid state 13C NMR and H1 NMR. Unique PXRD pattern, red shift in acid carbonyl stretching of Lesinurad in DMSO solvent, Urea co-crystal and parahydroxybenzoic acid co-crystals are the evidence of solvate and co-crystal formation. Urea co-crystal is further characterized using 13C solid state NMR. Deshielding of acid carbonyl carbon from δppm of 168.98 to 173.12 and shielding of urea carbonyl carbon from δppm of 169 to 164.56 indicates co-crystal formation between lesinurad and urea. DMSO solvate has shown 1.26 fold increase in Intrinsic dissolution rate measurement (IDR) over marketed Form-II and urea co-crystal. DMSO solvate, urea and 4-Hydroxy benzoic acid cocrystals of lesinurad are stable for six months at 40 °C and 75%RH.

Mechanism for the Reduced Dissolution of Ritonavir Tablets by Sodium Lauryl Sulfate

Sodium lauryl sulfate (SLS) is an anionic surfactant widely used in pharmaceutical research as a dissolution enhancer for poorly soluble drugs. When SLS was used in ritonavir (RTV) tablet formulation to improve wetting, dissolution of RTV was surprisingly deteriorated in acidic media. To understand this unexpected phenomenon, a systematic investigation, including solubility determination, intrinsic dissolution rate measurement, dissolution in an artificial stomach and duodenum apparatus, and solid-state characterization, revealed the formation of a poorly soluble salt, [RTV2+][LS−]2, in an acidic environment. Solubilization of the poorly soluble RTV salt was observed when the concentration of SLS exceeded the critical micelle concentration. Thus, precipitation of [RTV2+][LS−]2 at a low pH and in presence of a low SLS concentration can lead to deteriorated bioavailability. This unintended negative effect on dissolution should be carefully considered when using SLS in a tablet formulation of a basic drug that can be ionized in gastric fluid.

Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs

The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp >1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40 °C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F1), Kollidon VA/64 (F2) and Hydroxypropyl methyl cellulose acetate succinate (F3). When compared to a marketed product, Epitol® 200 mg tablets (F0), drug release after 60 min from formulations F1 (∼82%), F2 (∼95%) and F3 (∼95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F1–F3 than Epitol.

Using Salt Cocrystals to Improve the Solubility of Niclosamide

This Article reports the solvent-free synthesis and characterization of a number of different crystal forms of niclosamide (HNic), which is an API belonging to the Salicilamide class. The synthesized compounds are four new salt cocrystals (KNic·HNic·H2O, KNic·HNic·3H2O, NaNic·HNic·3H2O, NaNic·HNic·2H2O), a classic cocrystal with imidazole (IM) (HNic·IM), and two sodium salts, (NaNic·DMSO·H2O and NaNic·DMSO·2H2O). The peculiarity of these salt cocrystals is the API’s concomitant presence as both a neutral component and as a salt coformer and the fact that they interact via hydrogen bond formation. HNic’s poor aqueous solubility makes the enhancement of its dissolution rate via the modulation of its physical properties extremely important. All samples have been investigated using a combination of solid-state experimental techniques which provide complementary information on powdered samples. These techniques are X-ray powder diffraction, solid-state NMR, IR, and Raman. Single crystals were only obtained for KNic·HNic·H2O and NaNic·DMSO·2H2O. The nature of the adducts (whether salt or cocrystal), their stoichiometry and the presence of independent molecules in the unit cell of the other samples were thus all determined by means of solid-state NMR and the comparative analysis of 13C and 15N CPMAS (Cross-Polarization Magic Angle Spinning) and 1H MAS spectra. Furthermore, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate measurements completed the characterization and enabled us to evaluate the effects of microscopic changes (molecular packing, weak interactions, conformations, etc.) on the macroscopic properties (thermal stability and bioavailability) of the multicomponent forms. The results obtained indicate that the formation of salt cocrystals provides a reliable method with which to improve the HNic intrinsic dissolution rate.

Crystallization and Polymorphism of Felodipine

Two previously known polymorphs (forms I and II) and two new polymorphs (forms III and IV) of the calcium-channel blocker felodipine were obtained during attempts to cocrystallize the compound with a variety of potential cocrystal formers. A correlation was observed between the polymorphic outcome and the effective pH value in the presence of the cocrystal former, and it was possible subsequently to produce the four polymorphs by pH adjustment using H2SO4(aq) or NaOH(aq). This suggests that there is no distinct “structure-directing” role for the molecular additives present during the cocrystallization trials. The crystal structures of the new forms III and IV were determined using single-crystal X-ray diffraction. Forms I, II, and III were obtained in bulk form and characterized by a variety of analytical methods, including thermal analysis, solution calorimetry, intrinsic dissolution rate measurement, and solubility measurement. Form IV could be obtained only as a few isolated single crystals, and its cr...

Ionic Co-crystals of Organic Molecules with Metal Halides: A New Prospect in the Solid Formulation of Active Pharmaceutical Ingredients

Ionic co-crystals (ICCs) are constituted of inorganic salts and organic molecules. These crystals combine ionic interactions with classical supramolecular bonding such as hydrogen and dipole-bonding interactions. Such is the case of the hydrogen bonds between N–H and C═O dipoles in primary and secondary amides when these cocrystallize with an ionic material such as CaCl2. Here, we report our results of the preparation and characterization of a series of ICCs in which the molecular component is an active pharmaceutical ingredient (API) or a precursor of APIs, namely, barbituric acid, diacetamide, malonamide, nicotinamide, and piracetam, while the inorganic salt coformer is CaCl2. CaCl2 has been chosen, inter alia, for its nontoxicity and potential applications in the pharmaceutical field. Preparative methods include conventional crystallizations from solution, as well as slurry and solid state techniques (grinding and kneading). All crystal structures reported herein were determined either from single crystal diffraction data or from powder diffraction data, using simulated annealing procedures. Crystalline products were analyzed by differential scanning calorimetry, thermogravimetric analysis, and variable temperature X-ray powder diffraction. Intrinsic dissolution rate measurements were also performed on nicotinamide and piracetam ICCs.

Multiple approaches to pharmaceutical polymorphism investigation—A case study

Polymorph screening of Compound A, an investigational drug, revealed two anhydrous polymorphs (Forms I and II) and two monohydrates (Forms III and IV) of this pharmaceutical solid. The physiochemical properties of the four forms were characterized by thermal analysis, hot-stage microscopy, equilibrium solubility and intrinsic dissolution rate measurements, and X-ray powder diffraction. Inter-conversion relationship of the four forms was fully elucidated. Thermodynamic stability relationship was inferred from melting data for Form I and Form II and evaluated by van’t Hoff plot for Form III and Form IV. Form I and Form III were found to be the more stable anhydrous and hydrate form, respectively. Anhydrous Form I was selected for further pharmaceutical development.

Miniaturized Rotating Disk Intrinsic Dissolution Rate Measurement: Effects of Buffer Capacity in Comparisons to Traditional Wood’s Apparatus

The objective was to investigate the feasibility of using a miniaturized disk intrinsic dissolution rate (IDR) apparatus to determine the Biopharmaceutics Classification System (BCS) solubility class, and to develop an approach where IDR measurements performed in media of different buffer capacity could be compared. The disk IDR values of 14 model drugs were determined at 37 degrees C in US Pharmacopeia buffers at pH 1.2, 4.5, and 6.8. As little as 5 mg of drug were compressed in a die, with surface area of 0.071 cm(2), with the die assembly rotated at 100 rpm in 10 mL media. Drug concentration was measured by an in situ fiber optic ultraviolet method. The solubilities and pK(a)s were determined, and used to simulate dissolution profiles with a convective-diffusion-with-chemical-reaction model. The disk IDR values spanned six orders of magnitude (0.00014 to 114 mg min(-1) cm(-2)). The comparison of the miniaturized disk IDR values to published results using traditional dissolution bath apparatus indicated r (2) = 0.99. The results demonstrate that using 100-fold less drug does not sacrifice the quality of the measurement, and lends support to an earlier study Yu et al. (Int. J. Pharm. 270:221-227, 2004) that the disk IDR measurement may possibly serve as a surrogate for the BCS solubility classification.

Solubilization and dissolution of insoluble weak acid, ketoprofen: Effects of pH combined with surfactant

This study investigated the combined effect of pH and surfactant on the solubility and dissolution of ketoprofen (KP), a highly permeable and an ionizable and water-poorly soluble drug in gastrointestinal tract. The equilibrium solubility of KP was determined in buffers at the pH range from 4.0 to 6.8 and sodium lauryl sulfate (SLS) concentrations from 0% to 2.0%. Its intrinsic dissolution rate was measured in the same media using a rotating disk apparatus. A simple additive model accounting for the free unionized KP and ionized KP− forms, and their corresponding micellar forms was employed to study the in vitro solubility and dissolution behavior. Non-linear regression analysis showed that the proposed model agreed well with the experimental data, with Rsq=0.96 (P<0.0001) for the solubility study, and Rsq=0.98 (P<0.0001) for the intrinsic dissolution rate measurement. The pKa and cKP values are estimated as 4.76±0.00 and 0.253±0.05mg/mL, respectively, in good agreement with literature reports. The micellar solubilization coefficient k* for the unionized [KP]micelle is 757±165L/mol, whereas the value k** for the ionized [KP−]micelle is 9.88±6.70L/mol. The diffusion coefficients of various species: KP, KP−, [KP]micelle, and [KP−]micelle, are 7.68×10−6, 1.54×10−6, 2.32×10−7, and 2.13×10−20cm2/s, respectively. The maximum enhancement of solubilization is approximately 232-fold, while the maximum dissolution amplification is only 54-fold because of the smaller diffusivity of micellar species. The dramatic enhancement of in vitro solubility/dissolution attributable to an increase of pH and presence of SLS mimics the in vivo solubilization/dissolution behavior of KP along the gastrointestinal tract, when the pH increases from 1–2 in the stomach to 5–6 in the duodenum. The results suggest that the KP dissolves very rapidly in small intestine, implying that its absorption will be predominantly controlled by gastric emptying, and only minimally limited by the subsequent dissolution processes. This behavior is very similar to BCS I drugs, thus KP may be considered for possible waivers of bioequivalence.

Physical Characterization of Anhydrous and Hydrous Forms of the Hydrochloride Salt of BVT.5182 A Novel 5-HT6 Receptor Antagonist

ABSTRACTThe physicochemical properties of 1-benzenesulfonyl-4-(piperazin-1-yl)-indole hydrochloride, a novel 5-HT6 receptor antagonist for the treatment of obesity were characterized. Two solid state forms were identified at ambient conditions (23°C): an anhydrate form (1) and a hydrate form (2), with 1.5 moles of H2O. The latter easily dehydrates and rehydrates without affecting the crystal morphology. Investigations of the propensity for interconversion between the two forms reveal that a) conversion of 2→1 takes place above 145°C and that b) conversion of 1→2 only occurs after crystallization from supersaturated aqueous solutions at a water activity ≥0.94 or in the presence of comparable amounts of crystals of 2 in water at ambient conditions. However, in an equimolar suspension of 1 and 2 at 37°C no phase transformation was observed. Thus, the difference in chemical potential between the two forms is small. Form 1 was shown to have overall favorable solid state properties and, hence, considered the preferred form for continued pharmaceutical development. The characterization was performed by means of light microscopy, scanning electron microscopy, powder X-ray diffraction, FTIR/NIR-spectroscopy, differential scanning calorimetry, hot stage microscopy, thermogravimetry, dynamic vapor sorption, Karl Fischer water content determination, phase stability studies of suspensions, solubility, and intrinsic dissolution rate measurements.

Physicochemical Characterization of the Various Solid Forms of Carbovir, An Antiviral Nucleoside

Carbovir, which exhibits promising in-vitro activity against HIV, is shown to exist in five forms: I, II, III, IV, and V. Forms I-III and V were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot-stage microscopy (HSM), Karl Fischer titrimetry (KFT), powder X-ray diffraction (PXD), intrinsic dissolution rate (IDR) studies, heat of solution measurements (SC), scanning electron microscopy (SEM), Fourier-transform infrared (FTIR) spectroscopy, and water uptake at various relative humidities (water activities). Form IV could not be characterized fully, as it is stable only over a narrow temperature range (267-275 °C) which is immediately followed by melting and decomposition. With increasing temperature in DSC, forms I and V transformed successively to form III (195 °C), then to form II (220 °C), and then to form IV (275 °C). The PXD patterns, FTIR spectroscopy, IDR, and SC showed significant differences between these polymorphs. For each of the forms I, II, and III, there exists a critical value of relative humidity above which absorption of water proceeds steeply, leading to the formation of form V, which is more heavily hydrated than any of the other forms. Forms I and V each showed a two-step weight loss in TGA (24-120 °C), suggesting the presence of water molecules with two different binding energies probably corresponding to two different locations in the crystal lattice; HSM confirmed the dehydration. Thus, while forms I and V are hydrates, containing ca. 0.9 and 1.2 mol of water/mol of carbovir, respectively, from KFT, forms II-IV are different unsolvated polymorphic forms. Form I is a (pseudopolymorphic) hydrate which may have variable water stoichiometry. The order of the IDR values of compacted disks into water at 25 °C is form II ≫ form III > form I ∼ form V, corresponding to the order of free energy with respect to the aqueous solution. While the dissolution of forms I, III, and V was linear, the IDR of form II decreased after 15 min to a constant value, corresponding to conversion to form V. In contact with water, forms I and III also convert to form V but more slowly, beyond the 1 h time span of the IDR measurements. The order of the endothermic heats of solution into pH 12.4 glycine buffer is form V ∼ form I ≫ form III ∼ form II, corresponding to the reverse order of the enthalpy of the solid phases. ESEM micrographs showed the platy habits of forms I-III and V and the fractured surfaces of the desolvated polymorph, form II.

Influence of compaction on the intrinsic dissolution rate of modified acetaminophen and adipic acid crystals

Previous work has shown that aqueous crystallization of acetaminophen in the presence of p-acetoxyacetanilide or adipic acid in the presence of n-alkanoic acids (carbon number ⩾ 6) modifies the dissolution rate of free floating crystals per unit surface area in the USP Apparatus 2 (crystal intrinsic dissolution rate, i.e., crystal-IDR). The present work measures and compares the corresponding dissolution rates of compacted discs per unit surface area of disc (disc intrinsic dissolution rate, i.e., disc-IDR). The differences between the crystal IDRs (by factors of 1–2.4) of the acetaminophen samples almost disappeared with the disc-IDRs. This result confirms that crystal habit is the major factor which determines the intrinsic dissolution rate of acetaminophen crystals, rather than crystal energetics. On the other hand, differences between the crystal-IDRs of the adipic acid samples persisted, although somewhat reduced, among the disc-IDRs. This result confirms that the crystal energetics is the major factor which determines the intrinsic dissolution rate of adipic acid crystals. Significant changes in the dissolution behavior after compaction of the adipic acid samples suggest that compaction alters the nature, concentration and/or profile of the crystal defects that determine the crystal energetics. Implications in using the disc method for intrinsic dissolution rate measurement are discussed.