Optimizing Solubility and Permeability of a Biopharmaceutics Classification System (BCS) Class 4 Antibiotic Drug Using Lipophilic Fragments Disturbing the Crystal Lattice

Tehler, Ulrika; Fagerberg, Jonas H; Svensson, Richard; Larhed, Mats; Artursson, Per; Bergström, Christel A S

doi:10.1021/jm301721e

Cited by 51 publications

(31 citation statements)

References 19 publications

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“…A similarly low P e of 0.19 x 10 -6 cm/s for CIP was obtained by Tehler et al in Caco-2 studies. 63 Two-sample t tests were used to compare the results of the individual samples under both pH conditions, and in each case no statistically significant difference was found (see p-values in Table 1). The pI of CIP is around 7.4-7.5.…”

Section: Pampa Permeability Studymentioning

confidence: 99%

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

et al. 2017

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Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100C==, Carbopol and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully XCray amorphous following exposure to 90% RH at 25 oC, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug.Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCASC") and HPMCASCMG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability and antimicrobial activity.

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Section: Pampa Permeability Studymentioning

confidence: 99%

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

et al. 2017

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“…This is because, in order to increase the apparent solubility and the dissolution rate of the solid state-limited compounds, the strong crystal lattice has to be weakened. This can be achieved by using another polymorph (44), by introduction of co-formers to produce co-crystals (45,46), by selecting a salt of the drug (47), by making use of prodrug strategies (48), nanocrystal technologies (49,50) or by using amorphization (or formation of amorphous nanoparticles) (51–53). For a long period, amorphization was not the first choice because of the inherent instability issues resulting from the high energy form of the amorphous solid material (as indicated in the Background section).…”

Section: Current Status Of Research On Amorphous Formulationsmentioning

confidence: 99%

The Need for Restructuring the Disordered Science of Amorphous Drug Formulations

2017

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The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach.

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“…Two recent papers highlight the potential of these approaches and the attempts to build scientific bridges across the two communities. The first paper optimises the solubility of a BCS class 4 antibiotic drug using structural modifications to disrupt the crystal lattice, which was limiting the solubility;[15] the second paper uses co‐crystals to optimise the dissolution rate of a psychotropic drug with known dissolution challenges [16]…”

Section: Introductionmentioning

confidence: 99%