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During the OrBiTo project, our knowledge on the gastrointestinal environment has improved substantially and biorelevant media composition have been refined. The aim of this study was to propose optimized biorelevant testing conditions for modified release products, to evaluate the reproducibility of the optimized compendial apparatus III (USP apparatus III) and compendial apparatus IV (USP apparatus IV, open-loop mode) dissolution methods and to evaluate the usefulness of these methods to forecast the direction of food effects, if any, based on the results of two «ring» studies and by using two model modified release (MR) products, Ciproxin / Cipro XR and COREG CR. Six OrBiTo partners participated in each of the ring studies. All laboratories were provided with standard protocols, pure drug substance, and dose units. For the USP apparatus III, the dissolution methods applied to Ciproxin / Cipro XR, a monolithic MR product of an active pharmaceutical ingredient (API) with moderate aqueous solubility, were robust with low intra- and inter-laboratory data variability. Data from all partners were in line on a qualitative basis with food effect data in humans. For the USP apparatus IV, the dissolution methods applied to COREG CR, a multiparticulate, pH dependent, MR product of an API with low and pH dependent solubility led to high intra- and inter- laboratory data variability. Data from all partners were in line, on a qualitative basis, with the previously observed food effects in humans.

The pur­pose of this study was to con­duct an in­ter­lab­o­ra­tory ring-study, with six part­ners (aca­d­e­mic and in­dus­trial), in­ves­ti­gat­ing the mea­sure­ment of in­trin­sic dis­so­lu­tion rate (IDR) us­ing sur­face dis­so­lu­tion imag­ing (SDI) equip­ment. Mea­sure­ment of IDR is im­por­tant in phar­ma­ceu­ti­cal re­search as it pro­vides char­ac­ter­is­ing in­for­ma­tion on drugs and their for­mu­la­tions. This work al­lowed us to as­sess the SDI’s in­ter­lab­o­ra­tory per­for­mance for mea­sur­ing IDR us­ing a de­fined stan­dard op­er­at­ing pro­ce­dure (see sup­port­ing in­for­ma­tion) and six drugs as­signed as low (tadalafil, bromocrip­tine me­sy­late), medium (carvedilol, in­domethacin) and high (ibupro­fen, val­sar­tan) sol­u­bil­ity com­pounds. Fasted State Sim­u­lated In­testi­nal Fluid (FaS­SIF) and blank FaS­SIF (with­out sodium tau­ro­cholate and lecithin) (pH 6.5) were used as me­dia. Us­ing the stan­dard­ised pro­to­col an IDR value was ob­tained for all com­pounds and the re­sults show that the over­all IDR rank or­der matched the sol­u­bil­ity rank or­der. In­ter­lab­o­ra­tory vari­abil­ity was also ex­am­ined and it was ob­served that the vari­abil­ity for lower sol­u­bil­ity com­pounds was higher, co­ef­fi­cient of vari­a­tion >50%, than for in­ter­me­di­ate and high sol­u­bil­ity com­pounds, with the ex­cep­tion of in­domethacin in FaS­SIF medium. In­ter lab­o­ra­tory vari­abil­ity is a use­ful de­scrip­tor for un­der­stand­ing the ro­bust­ness of the pro­to­col and the sys­tem vari­abil­ity. On com­par­i­son to an­other pub­lished small-scale IDR study the rank or­der­ing with re­spect to dis­so­lu­tion rate is iden­ti­cal ex­cept for the high sol­u­bil­ity com­pounds. This re­sults in­di­cates that the SDI ro­bustly mea­sures IDR how­ever, no rec­om­men­da­tion on the use of one small scale method over the other is made.

Aqueous solubility is an essential characteristic assessed during drug development to determine a compound's drug-likeness since solubility plays an important pharmaceutical role. However, nearly half of the drug candidates discovered today display poor water solubility; therefore methods have to be applied to increase solubility. Solubility determination using the CheqSol method is a novel rapid solubility screening technique for ionisable compounds. The aim of this study is to determine if the CheqSol method can be employed to determine solubility increases of four test drugs (ibuprofen, gliclazide, atenolol and propranolol) induced by non-ionising excipients such as hydroxypropyl-β-cyclodextrin and poloxamers 407 and 188. CheqSol assays were performed for the drugs alone or in combination with varying solubiliser concentrations. The measured intrinsic solubility of all four drugs increased with all the excipients tested in an excipient concentration dependent manner providing results consistent with previous literature. The results demonstrate that it may be possible to use this method to determine the solubility increases induced by non-ionic solubilising excipients with results that are comparable to standard equilibrium based solubility techniques. Since the technique is automated and requires only small drug quantities it may serve as a useful solubility or formulation screening tool providing more detailed physicochemical information than multiwell plate or similar visual systems.

Objectives The aim of this study was to determine the influence of non-ionisable excipients hydroxypropyl-β-cyclodextrin (HPβCD) and poloxamers 407 and 188 on the supersaturation and precipitation kinetics of ibuprofen, gliclazide, propranolol and atenolol induced through solution pH shifts using the CheqSol method. Methods The drug's kinetic and intrinsic aqueous solubilities were measured in the presence of increasing excipient concentrations using the CheqSol method. Experimental data rate of change of pH with time was also examined to determine excipient-induced parachute effects and influence on precipitation rates. Key findings The measured kinetic and intrinsic solubilities provide a determination of the influence of each excipient on supersaturation index, and the area under the CheqSol curve can measure the parachute capability of excipients. The excipients influence on precipitation kinetics can be measured with novel parameters; for example, the precipitation pH or percentage ionised drug at the precipitation point, which provide further information on the excipient-induced changes in precipitation performance. Conclusion This method can therefore be employed to measure the influence of non-ionisable excipients on the kinetic solubility behaviour of supersaturated solutions of ionisable drugs and to provide data, which discriminates between excipient systems during precipitation.