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      Dissolution Enhancement of Atorvastatin Calcium by Cocrystallization

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          Abstract

          Purpose: To enhance the dissolution rate of the poorly soluble drug atorvastatin calcium (ATC) by cocrystallization with selected coformers. Enhancement of the dissolution rate and solubility of the drug, which is classified as Class II of the Biopharmaceutical Classification System (BCS), is expected to enhance the bioavailability.

          Methods: Two methods were used for preparing the cocrystals, solvent drop grinding (SDG) and solvent evaporation (SE) method using 1:1, 1:3, and 1:10 drug-coformer molar ratios. Glucosamine hydrochloride (GluN) and nicotinamide (NIC) were investigated as coformers. The cocrystals, their physical mixtures, and the raw ATC were characterized by fourier transform infrared (FTIR spectroscopy), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), mass spectroscopy (MS), scanning electron microscopy (SEM), solubility, and dissolution rate studies.

          Results: SDG and SE were effective in improving the dissolution rate of ATC with both coformers. Drug: coformer ratio 1:3 was optimum. The solubility values for ATC, GluN-, and NIC-cocrystals were 26, to 35 and 50 µg/mL, respectively. The dissolution rate of ATC from cocrystals was > 90% after 5 minutes, compared to 41% untreated ATC.

          Conclusion: Cocrystallization significantly improved the solubility and dissolution, in comparison to the untreated ATC.

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          Clinical pharmacokinetics of atorvastatin.

          Hans Lennernäs (2003)
          Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.
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            A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals.

            Gordon L. Amidon, Ana Martinez (2002)
            This article provides an overview of the patient-specific and drug-specific variables that can affect drug absorption following oral product administration. The oral absorption of any chemical entity reflects a complex spectrum of events. Factors influencing product bioavailability include drug solubility, permeability, and the rate of in vivo dissolution. In this regard, the Biopharmaceutics Classification System has proven to be an important tool for predicting compounds likely to be associated with bioavailability problems. It also helps in identifying those factors that may alter the rate and extent of drug absorption. Product bioavailability can also be markedly influenced by patient attributes such as the integrity of the gastrointestinal tract, physiological status, site of drug absorption, membrane transporters, presystemic drug metabolism (intrinsic variables), and extrinsic variables such as the effect of food or concomitant medication. Through an awareness of a drug's physicochemical properties and the physiological processes affecting drug absorption, the skilled pharmaceutical scientist can develop formulations that will maximize product availability. By appreciating the potential impact of patient physiological status, phenotype, age, gender, and lifestyle, dosing regimens can be tailored to better meet the needs of the individual patient.
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              Control and interconversion of cocrystal stoichiometry in grinding: stepwise mechanism for the formation of a hydrogen-bonded cocrystal

              Shyam Karki, Tomislav Friscić, William Jones (2009)
              Article 0 comments Cited 55 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Adv Pharm Bull
                Journal ID (iso-abbrev): Adv Pharm Bull
                Journal ID (publisher-id): Adv Pharm Bull
                Journal ID (pmc): APB
                Journal ID (publisher-id): TBZMED
                Title: Advanced Pharmaceutical Bulletin
                Publisher: Tabriz University of Medical Sciences
                ISSN (Print): 2228-5881
                ISSN (Electronic): 2251-7308
                Publication date (Print): October 2019
                Publication date (Electronic): 24 October 2019
                Volume: 9
                Issue: 4
                Pages: 559-570
                Affiliations
                Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, Health Sciences Center, Gabriya, Kuwait.
                Author notes
                [* ] Corresponding Author: Aly Nada, Tel: +965 24636072 (Office), Fax: +965 24636843, Email: alynada@ 123456hsc.edu.kw
                Author information
                https://orcid.org/0000-0003-4628-3475
                Article
                DOI: 10.15171/apb.2019.064
                PMC ID: 6912187
                PubMed ID: 31857959
                SO-VID: d5cbf194-6cd8-47a9-978f-063fe31d21b9
                Copyright © © 2019 The Author (s)
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, as long as the original authors and source are cited. No permission is required from the authors or the publishers.

                History
                Date received : 17 March 2019
                Date revision received : 29 May 2019
                Date accepted : 01 June 2019
                Page count
                Figures: 8, Tables: 2, References: 40, Pages: 12
                Categories
                Subject: Research Article

                Keywords: atorvastatin,glucosamine,nicotinamide,cocrystallization,characterization
                Data availability:
                Keywords: atorvastatin, glucosamine, nicotinamide, cocrystallization, characterization

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