Formulation Possibilities of a Weak Base with a Narrow Solubility Range

Venczel, Márta; Szvoboda, Ida; Podányi, Benjamin; Valente, Delphine; Ménégotto, J.; Pintye‐Hódi, Klára; Ujhelyi, Gabriella

doi:10.1021/cg200462g

Cited by 11 publications

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References 17 publications

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“…The aims of this thesis are  to explore and apply the synergies among chemical and pharmaceutical tools in case of a development of pharmaceutical co-crystals on the example of SAR1 compound (origin molecule of Sanofi) [10,11] …”

Section: Aimsmentioning

confidence: 99%

Section: Pharmaceutical Processability -Co-crystal Integrity and Pharmentioning

confidence: 99%

“…One of the most difficult pharmaceutical formulation tasks is to improve the absorption of a weak base with poor and pH-dependent solubility properties [8]; however, some combined chemical and formulation approaches give the possibility to reach this goal [10]. …”

Section: Introductionmentioning

confidence: 99%

“…In addition, the influence of Cremophor ELP on physical stability and dissolution was studied. Cremophor ELP is commonly used as solubiliser and is known to ensure the integrity of the co-crystals [10].Cremophor ELP has been demonstrated to be a well tolerated pharmaceutical excipient via oral route [86,87]. SAR1 fumaric acid co-crystal was used as model active pharmaceutical ingredient in the present study.…”

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confidence: 99%

“…SAR1 fumaric acid co-crystal was used as model active pharmaceutical ingredient in the present study. Increased bioavailability of fumaric acid co-crystal versus the free base was confirmed in a pharmacokinetic study [10]. The integrity of the fumaric acid cocrystal of SAR1 active pharmaceutical ingredient was studied after a wet granulation process [88,90] with four formulations containing the same qualitative and quantitative composition.…”

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confidence: 99%

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Pharmaceutical development of co-crystals

Venczel

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EARLY DRUG FORMULATION -FORMULATION POSSIBILITIES OF List of tables AIMSThe aims of this thesis are former has ten times higher solubility than the drug itself. However high aqueous solubility of co-crystal forms can lead to rapid convervation and hinter performance [20] that is why one of the main role of formulation experts is to work in a strong collaboration with chemical and analytical experts to protect physical integrity of co-crystals during the formulation work. Designing of co-crystalsCo-crystals are supramolecular homo-(I and III) or heterosynthons (II and IV) presented on is not suitable to reach the sink condition for active pharmaceutical ingredients, which are practically insoluble in aqueous solutions. In contrast to the past, when the majority of research compounds had a relatively small molecular weight and acceptable solubility, the Three active pharmaceutical ingredients were evaluated and compared. These are: SAR1 as a weak base, its di-HCl salt and its co-crystal with fumaric acid. All API study batches were manufactured in laboratory scale from 10 g to 30 g. Resynthesis batch of the fumaric acid cocrystal was manufactured in 0.7 kg scale. Active pharmaceutical ingredient in the area of flow-through dissolutionAn origin molecule of Sanofi coded as a "C" model material was used for FaSSIF (fasted state simulated intestinal fluid) and FeSSIF (fed state simulated intestinal fluid) dissolution study.The same "C" model API and its sevaral salt forms were applied to show the benefits of flow through dissolution during salt selection studies. BuffersBuffer solutions were prepared according to the USP and Ph. Eur. recommendations 39, 40. Pharmaceutical excipientsCremophor ELP was ordered from BASF. Cremophor ELP, a purifed grade of Cremophor EL was specially developed for sensitive active ingredients, as the higher purity was found to improve their stability 41. Tween 80, lactic acid, citric acid, Span 85, PEG 200, sodium hydroxide were purchased from Merck while Eudragit L100-55 was ordered from Evonic.Some pharmaceutical excipients such as mannitol, sulfobuthyl  cyclodextrin, vitamin E TPGS, PVP K25, sodium docusate, Miglyol 812 N, sodium dodecyl sulfate, methyl cellulose, HPMC, crospovidone, microcrystalline cellulose, magnesium stearate and colloidal silica anhydrous were ordered from the internal warehouse of Sanofi. METHODS Chemical manufacturing SAR1 as a fumaric acid co-crystalThe reactor was charged with acetone (12 L), SAR1 base Form III (592 g, 1.29 mol) and fumaric acid (600 g, 5.16 mol). The slurry was stirred at room temperature for 24 hours, the crystals were filtered off, washed with water (1 L) and ethanol (1 L), and dried in a vacuum at 80°C for five hours. Yield: 723 g (94.0%) pale yellow powder [42]. The purity of the product was: 98.9% (HPLC). SAR1 as a dihydrochloride saltSAR1 (29 g) was added to methanol (1370 ml) under nitrogen. The suspension of API was stirred in Ultra-Turrax system for 30 minutes at room temperature. The concentrated hydrochloric acid (8.03 ml, 2....

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Section: Aimsmentioning

confidence: 99%

Section: Pharmaceutical Processability -Co-crystal Integrity and Pharmentioning

confidence: 99%