Determination of excipient based solubility increases using the CheqSol method

Etherson, Kelly; Halbert, Gavin; Elliott, Moira A.

doi:10.1016/j.ijpharm.2014.02.007

Cited by 9 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During this phase, the rate of change of pH with respect to time (dpH/d t ) is measured and sample results for propranolol are presented in Figure for the drug on its own and in the presence of selected concentrations of each of the three excipients employed. It is obvious that the presence of the excipients increases the measured solubility by shifting the equilibrium chasing point to higher concentrations . Based on the dpH/d t data, the CheqSol method determines precipitation parameters (precipitation concentration, i.e.…”

Section: Resultsmentioning

confidence: 99%

“…For the intrinsic solubility, these measurements were comparable to previously published traditional shake-flask methods. [27] However, during the conduct of this study, it was noted other experimental parameters were changing [26] and indicated that as the CheqSol method was dynamic, [16] it may also be determining spring and parachute type behaviour and the precipitation kinetics. In this study, we have employed the CheqSol method to examine the influence of the non-ionising excipients, hydroxypropyl-b-cyclodextrin and the poloxamers 407 and 188 on the precipitation behaviour of four test drugs: the acids' ibuprofen and gliclazide and the bases' atenolol and propranolol.…”

Section: Measures Of Solubilitymentioning

confidence: 85%

“…The shift of pH in the presence of excipients has been previously employed in potentiometric studies of cyclodextrin inclusion complexes to determine binding constants and to study the interaction of drugs with surfactants and lipid phases to determine partition coefficients. Changes in the measured slope of the dpH/d t line indicate an excipient effect on the assay's kinetic behaviour, which is to be expected as both excipient types are known to influence the solution behaviour and solubility of small molecules . Although precipitation and determination of precipitation rate is an integral feature of the dynamic nature of CheqSol, which has been employed to determine the solubility of multiple drugs and the influence of polymers on precipitation, no data on the measured precipitation rates have been presented.…”

Section: Discussionmentioning

confidence: 99%

“…[25] Recently, we have employed this technique to determine solubility increases associated with the solubility enhancing excipients hydroxypropyl-b-cyclodextrin (HPbCD) and the poloxamers 407 and 188. [26] As these excipients are non-ionisable, the CheqSol method was able to measure their influence on the solubility of test ionisable drugs, determining excipient concentration dependent increases in both intrinsic and kinetic solubility values. For the intrinsic solubility, these measurements were comparable to previously published traditional shake-flask methods.…”

Section: Measures Of Solubilitymentioning

confidence: 99%

“…This technique, which was initially aimed at early drug development and candidate screening studies, should however be applicable to situations where the determination of solubility is required such as parenteral formulation development or crystallisation . Recently, we have employed this technique to determine solubility increases associated with the solubility enhancing excipients hydroxypropyl‐β‐cyclodextrin (HPβCD) and the poloxamers 407 and 188 . As these excipients are non‐ionisable, the CheqSol method was able to measure their influence on the solubility of test ionisable drugs, determining excipient concentration dependent increases in both intrinsic and kinetic solubility values.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method

Etherson

Halbert

Elliott

2016

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

Objectives: The aim of this study was to determine the influence of non-ionisable excipients hydroxypropyl--cyclodextrin (HPCD) 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 solubility was measured in the presence of increasing excipient concentrations using the CheqSol solubility method. Experimental data for example 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 ionized 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 behavior of supersaturated solutions of ionisable drugs and to provide data, which discriminates between excipient systems during precipitation.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Measures Of Solubilitymentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Measures Of Solubilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method

Etherson

Halbert

Elliott

2016

Journal of Pharmacy and Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

Machine learning in prediction of intrinsic aqueous solubility of drug‐like compounds: Generalization, complexity, or predictive ability?

Lovrić

Pavlović

Žuvela

et al. 2021

Journal of Chemometrics

View full text Add to dashboard Cite

We present a collection of publicly available intrinsic aqueous solubility data of 829 drug-like compounds. Four different machine learning algorithms (random forests [RF], LightGBM, partial least squares, and least absolute shrinkage and selection operator [LASSO]) coupled with multistage permutation importance for feature selection and Bayesian hyperparameter optimization were used for the prediction of solubility based on chemical structural information. Our results show that LASSO yielded the best predictive ability on an external test set with a root mean square error (RMSE) (test) of 0.70 log points, an R 2 (test) of 0.80, and 105 features. Taking into account the number of descriptors as well, an RF model achieves the best balance between complexity and predictive ability with an RMSE(test) of 0.72 log points, an R 2 (test) of 0.78, and with only 17 features. On a more aggressive test set (principal component analysis [PCA]-based split), better generalization was observed for the RFmodel. We propose a ranking score for choosing the best model, as test set performance is only one of the factors in creating an applicable model. The ranking score is a weighted combination of generalization, number of features, and test performance. Out of the two best learners, a consensus model was built exhibiting the best predictive ability and generalization with RMSE(test) of 0.67 log points and a R 2 (test) of 0.81.

show abstract

Automated assays for thermodynamic (equilibrium) solubility determination

Sou

Bergström

2018

Drug Discovery Today: Technologies

View full text Add to dashboard Cite

Solubility is a crucial physicochemical property for drug candidates and is important in both drug discovery and development. Poor solubility is detrimental to absorption after oral administration and can mask compound activity in bioassays in various ways. Hence, solubility liabilities should ideally be identified as early as possible in the drug development process. With the increasing number of compounds as potential drug candidates, automated thermodynamic solubility assays for high throughput screening enabling rapid evaluation of a large number of compounds are becoming increasingly important. This review discusses the current status of the most widely used automated assays for thermodynamic solubility, followed by recent high throughput measurements of properties related to solubility (e.g. dissolution rate and supersaturation) and a brief overview of predictive computational methods for thermodynamic solubility reported in the literature.

show abstract

Determination of excipient based solubility increases using the CheqSol method

Cited by 9 publications

References 31 publications

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method

Machine learning in prediction of intrinsic aqueous solubility of drug‐like compounds: Generalization, complexity, or predictive ability?

Automated assays for thermodynamic (equilibrium) solubility determination

Contact Info

Product

Resources

About