scholarly journals Investigation of possible solubility and dissolution advantages of cocrystals, I: Aqueous solubility and dissolution rates of ketoconazole and its cocrystals as functions of pH

ADMET & DMPK ◽  
2019 ◽  
Vol 7 (2) ◽  
pp. 106-130
Author(s):  
Jaydip M. Vasoya ◽  
Ankita V. Shah ◽  
Abu T.M. Serajuddin
Keyword(s):  
Succinic Acid ◽  
Fumaric Acid ◽  
Aqueous Solubility ◽  
Free Base ◽  
Dissolution Rates ◽  
Basic Drug ◽  
Intrinsic Dissolution ◽  
Aqueous Suspensions ◽  
Ph Conditions ◽  
Solubility Profiles

Since there are conflicting reports in the literature on solubility and dissolution advantages of cocrystals over free forms, we systematically studied solubility and intrinsic dissolution rates of a weakly basic drug, ketoconazole, and its cocrystals with fumaric acid and succinic acid as functions of pH to determine what advantages cocrystals provide. pH-solubility profiles were determined in two different ways: one by lowering pH of ketoconazole aqueous suspensions using HCl, fumaric acid and succinic acid, and the other by adjusting pH of cocrystal suspensions using respective coformer acids or NaOH. Similar pH-solubility profiles were obtained whether free base or cocrystals were used as starting materials to determine solubility. With the addition of fumaric and succinic acids to aqueous suspensions of free base to lower pH, the maximum solubility (pHmax) was reached at pH ~3.5-4.0, below which the solubility decreased and cocrystals formed. The solubility, however, continued increasing when HCl was added to ketoconazole suspension as no cocrystal or salt was formed. During determination of cocrystal solubility, a conversion to free base was observed when pH was raised above pHmax. Thus, pH-solubility profiles of cocrystals resembled solubility profiles commonly encountered with salts. Above pHmax, both free base and cocrystal had similar solubility under identical pH conditions; the solubility of cocrystal was higher only if the pH differed. In contrast, intrinsic dissolution rates of cocrystals at pH>pHmax under identical bulk pH were much higher than that of free ketoconazole since cocrystals had lower microenvironmental pH at the dissolving surface, where the solubility was high. Thus, cocrystals of basic drugs can potentially provide higher dissolution rates under intestinal pH conditions.

scholarly journals Identification and Pharmaceutical Characterization of a New Itraconazole Terephthalic Acid Cocrystal

Pharmaceutics ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 741 ◽  
Author(s):  
Ricardo Machado Cruz ◽  
Tereza Boleslavská ◽  
Josef Beránek ◽  
Eszter Tieger ◽  
Brendan Twamley ◽  
...  
Keyword(s):  
Terephthalic Acid ◽  
Rank Order ◽  
Parent Drug ◽  
Aqueous Solubility ◽  
Pharmaceutical Formulations ◽  
Active Pharmaceutical Ingredient ◽  
Water Soluble ◽  
Dissolution Rates ◽  
Intrinsic Dissolution ◽  
Aqueous Conditions

The crystallization of poorly soluble drug molecules with an excipient into new solid phases called cocrystals has gained a considerable popularity in the pharmaceutical field. In this work, the cocrystal approach was explored for a very poorly water soluble antifungal active, itraconazole (ITR), which was, for the first time, successfully converted into this multicomponent solid using an aromatic coformer, terephthalic acid (TER). The new cocrystal was characterized in terms of its solid-state and structural properties, and a panel of pharmaceutical tests including wettability and dissolution were performed. Evidence of the cocrystal formation was obtained from liquid-assisted grinding, but not neat grinding. An efficient method of the ITR–TER cocrystal formation was ball milling. The stoichiometry of the ITR–TER phase was 2:1 and the structure was stabilized by H-bonds. When comparing ITR–TER with other cocrystals, the intrinsic dissolution rates and powder dissolution profiles correlated with the aqueous solubility of the coformers. The rank order of the dissolution rates of the active pharmaceutical ingredient (API) from the cocrystals was ITR–oxalic acid > ITR–succinic acid > ITR–TER. Additionally, the ITR–TER cocrystal was stable in aqueous conditions and did not transform to the parent drug. In summary, this work presents another cocrystal of ITR that might be of use in pharmaceutical formulations.

Metabolites of Aspergillus indicus: The structure and some aspects of the biosynthesis of dihydrocanadensolide

1968 ◽  
Vol 21 (11) ◽  
pp. 2775 ◽  
Author(s):  
AJ Birch ◽  
AA Qureshi ◽  
RW Rickards
Keyword(s):  
Succinic Acid ◽  
Fumaric Acid ◽  
Pyruvic Acid ◽  
Kojic Acid ◽  
Synthetic Medium ◽  
Nitropropionic Acid

Aspergillus indicus grown on a semi-synthetic medium produces a number of metabolites including kojic acid, succinic acid, fumaric acid, β-nitropropionic acid, indazonic acids, fumaryl-~danine, and dihydrocanadensolide. The last compound is shown to have the formula (I) and is biosynthesized in part from "acetate" units; the rest of the molecule may come from pyruvic acid.

Solubilities and intrinsic dissolution rates of sulphamethoxazole and trimethoprim

1987 ◽  
Vol 39 (4) ◽  
pp. 246-251 ◽  
Author(s):  
Rajudin Dahlan ◽  
Charles Mcdonald ◽  
V. Bruce Sunderland
Keyword(s):  
Dissolution Rates ◽  
Intrinsic Dissolution

Powder Dissolution Method for Estimating Rotating Disk Intrinsic Dissolution Rates of Low Solubility Drugs

2009 ◽  
Vol 26 (9) ◽  
pp. 2093-2100 ◽  
Author(s):  
Konstantin Tsinman ◽  
Alex Avdeef ◽  
Oksana Tsinman ◽  
Dmytro Voloboy
Keyword(s):  
Rotating Disk ◽  
Dissolution Rates ◽  
Intrinsic Dissolution ◽  
Dissolution Method ◽  
Low Solubility ◽  
Low Solubility Drugs

scholarly journals The Role of Functional Excipients in Solid Oral Dosage Forms to Overcome Poor Drug Dissolution and Bioavailability

Pharmaceutics ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 393 ◽  
Author(s):  
Jannes van der Merwe ◽  
Jan Steenekamp ◽  
Dewald Steyn ◽  
Josias Hamman
Keyword(s):  
Dissolution Rate ◽  
Solid Dispersions ◽  
Aqueous Solubility ◽  
Dosage Forms ◽  
Oral Dosage ◽  
Drug Dissolution ◽  
Specific Reference ◽  
Dissolution Rates ◽  
Bioavailability Enhancement ◽  
Poor Solubility

Many active pharmaceutical ingredients (APIs) exhibit poor solubility and low dissolution rates in aqueous environments such as the luminal fluids of the gastrointestinal tract. The oral bioavailability of these compounds is usually very low as a result of their poor solubility properties. In order to improve the bioavailability of these poorly soluble drugs, formulation strategies have been applied as a means to improve their aqueous solubility and dissolution rates. With respect to formulation approaches, excipients can be incorporated in the formulation to assist in the dissolution process of the drug, or specialized dosage forms can be formulated that improve dissolution rate through various mechanisms. This paper provides an overview of selected excipients (e.g., alkalinizing agents, surfactants and sugars) that can be used in formulations to increase the dissolution rate as well as specialized dosage forms such as self-emulsifying delivery systems and formulation techniques such as inclusion complexes and solid dispersions. These formulation approaches are discussed with available examples with specific reference to positive outcomes in terms of drug solubility and bioavailability enhancement.

Simultaneous Gas Chromatographic Determination of Carboxylic Acids in Soft Drinks and Jams

1985 ◽  
Vol 68 (5) ◽  
pp. 902-905
Author(s):  
Taizo Tsuda ◽  
Hiroshi Nakanishi ◽  
Takashi Morita ◽  
Junko Takebayashi
Keyword(s):  
Benzoic Acid ◽  
Succinic Acid ◽  
Tartaric Acid ◽  
Carboxylic Acids ◽  
Fumaric Acid ◽  
Malic Acid ◽  
Sorbic Acid ◽  
Chromatographic Determination ◽  
Dehydroacetic Acid

Abstract A method was developed for simultaneous gas chromatographic determination of sorbic acid, dehydroacetic acid, and benzoic acid used as preservatives, and succinic acid, fumaric acid, malic acid, and tartaric acid used as acidulants in soft drinks and jams. A sample was dissolved in NH4OH-NH4CI pH 9 buffer solution, and an aliquot of the solution was passed through a QAE-Sephadex A 25 column. The column was washed with water, and the carboxylic acids were eluted with 0.1N HC1. Sorbic acid, dehydroacetic acid, and benzoic acid were extracted with ethyl ether-petroleum ether (1 + 1), and determined on a 5% DEGS + 1% H3PO4 column. Succinic acid, fumaric acid, malic acid, and tartaric acid in the lower layer were derivatized with N,0- bis(trimethylsilyl)acetamide and trimethylchlorosilane, and determined on a 3% SE-30 column. Recoveries from soft drink and jam samples fortified with 0.1% each of 7 carboxylic acids ranged from 92.4 to 102.6% for preservatives, and from 88.1 to 103.2% for acidulants.

scholarly journals Comparison and Modeling of Aqueous Dissolution Rates of Various Uranium Oxides

1996 ◽  
Vol 465 ◽  
Author(s):  
S. A. Steward ◽  
E. T. Mones
Keyword(s):  
Dissolution Rate ◽  
Atmospheric Oxygen ◽  
Fold Increase ◽  
Stable Phase ◽  
Uranium Oxides ◽  
Spent Fuel ◽  
Geologic Repository ◽  
Dissolution Rates ◽  
Intrinsic Dissolution ◽  
Carbonate Concentration

ABSTRACTThe purpose of this work has been to measure and model the intrinsic dissolution rates of uranium oxides under a variety of well-controlled conditions that are relevant to a geologic repository. When exposed to air at elevated temperature, spent fuel may form the stable phase U3O8. Dehydrated schoepite, UO3H2O, has been shown to exist in drip tests on spent fuel.Equivalent sets of U3O8 and UO3H2 dissolution experiments allowed a systematic examination of the effects of temperature (25–75°C), pH (8–10) and carbonate (2–200×10−4 molar) concentrations at atmospheric oxygen conditions.Results indicate that UO3H2O has a much higher dissolution rate (at least ten-fold) than U3O8 under the same conditions. The intrinsic dissolution rate of unirradiated U3O8 is about twice that of UO2. Dissolution of both U3O8 and UO3.H2O shows a very high sensitivity to carbonate concentration. Present results show a 25 to 50-fold increase in room-temperature UO3H2O dissolution rates between the highest and lowest carbonate concentrations.As with the UO2 dissolution data the classical observed chemical kinetic rate law was used to model the U3O8 dissolution rate data. The pH did not have much effect on the models, in agreement with the earlier analysis of the UO2 and spent fuel dissolution data,. However, carbonate concentration, not temperature, had the strongest effect on the U3O8 dissolution rate. The U3O8 dissolution activation energy was about 6000 cal/mol, compared with 7300 and 8000 cal/mol for spent fuel and UO2 respectively.

scholarly journals Solubility analysis of venlafaxine hydrochloride polymorphs by shake-flask method and real time monitoring

2019 ◽  
Vol 89 (2) ◽  
pp. 88-96
Author(s):  
Krisztina Takács-Novák ◽  
Dóra Tempfli ◽  
Dóra Csicsák ◽  
Gergely Völgyi ◽  
Enikő Borbás ◽  
...  
Keyword(s):  
Raman Spectroscopy ◽  
Real Time ◽  
Shake Flask ◽  
Fiber Optic ◽  
Solid Phase ◽  
Aqueous Solubility ◽  
Dissolution Kinetic ◽  
Free Base ◽  
Venlafaxine Hydrochloride ◽  
Ph Range

Aims: The aqueous solubility of two polymorphic forms of venlafaxine hydrochloride was investigated. Methods: The pH-dependent solubility (SpH) over a wide pH range was measured by saturation shake-flask (SSF) method at 25 °C. The solubility of the free base form was depicted by the intrinsic solubility (So). To identify the solid form present at the solubility equilibrium, X-ray powder diffraction (XRPD) and Raman spectroscopy was carried out. The dissolution was studied using real time concentration monitoring applying fiber optic UV probes. Results: No difference was found in the SpH values of Form I and Form II, in the pH range 7.5-12. Solid phase isolated from pH 10-12 suspensions was identified as free base by XRPD and Raman spectroscopy. Precipitates separated from pH 7-8 samples were also identical product. The transition of polymorphs to the free base was supported by the real time dissolution analysis. Conclusion: In this study we demonstrated a good agreement of equilibrium solubility measured by SSF method and in-situ UV fiber optic method. µDISS ProfilerTM has the advantage to provide much more information about dissolution process; with this approach the dissolution kinetic, the supersaturation and the time needed to reach the equilibrium can be easily monitored.

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