Ratio solubility-dose

GETTING STARTED SOLUBILITY AND THE DOSE SOLUBILITY RATIO... 

Figure 1 Using the dose solubility ratio and solubility as a guide to assessing the level of formulation challenge.

Rinaki E, Valsami G, Macheras P. Quantitative biophannaceutics classification system the central role of dose/solubility ratio. Pharm Res 2003 20(12) 1917-1925. 

In fact, it will be shown below that MDT is dependent on the dose-solubility ratio if one takes into account the dose qo actually utilized [90]. Also, it will be shown that the widely used (5.15) applies only to a special limiting case. Multiplying both parts of (5.1) by V/qo (volume of the dissolution medium/actual dose), one gets the same equation in terms of the fraction of the actual dose of drug dissolved, [Pg.98]

Both sides of the last two equations are divided by qo/V, and c(t) and cs are substituted by the fraction ip (t) of dose dissolved and the dimensionless dose-solubility ratio 9, respectively, yielding... 

Lansky, P. and Weiss, M., Does the dose-solubility ratio affect the mean dissolution time of drugs Pharmaceutical Research, Vol. 16, No. 9, 1999, pp. 1470-1476. 

Rinaki, E., Valsami, G., and Macheras, P., Quantitative biopharmaceutics classification system The central role of dose/solubility ratio, Pharmaceutical Research, Vol. 20, No. 12, 2003, pp. 1917-1925. 

The dose solubility ratio should be increased from 250 to 500 ml, particularly at pH values of 4.5 and 6.8, which are representative of the small intestine where the fluid volume is greater than the stomach. 

Dosage forms of APIs with high solubility at pH 6.8 but not at pH 1.2 or 4.5 and with high permeability (by definition, some but not all BCS Class 2 compounds with weak acidic properties) are eligible for a biowaiver based on BCS provided that criteria (b), (c) and (d) described in section 9.2. are met, that the API has high permeability (i.e. the fraction absorbed is 85% or greater) and a dose solubility ratio of 250 ml or less at pH 6.8, and that the multisource product ... 

For multisource products containing Class 2 APIs with dose solubility ratios of 250 ml or less at pH 6.8, the excipients should additionally be critically evaluated in terms of type and amoimts, e.g. of surfactants, in the formulation. Further, if the is critical to the therapeutic efficacy of the API, the risk of reaching an inappropriate biowaiver decision and its associated risks to public health and for individual patients may be deemed unacceptable. 

The reason for the 250-ml cut-off criterion for the dose solubility ratio is that in pharmacokinetic bioequivaience studies, the API formulation is to be ingested with a large glass of water (8 ounces corresponds to about 250 ml). If the highest orally administered dose can be completely dissolved in this amount of water, independent of the physiological pH value (hence the determination over the pH range 1-7.5), solubility problems are not expected to hinder the uptake of the API in the small intestine. 

When an API shows a dose solubility ratio of 250 ml or lower at 37 °C over a pH range of 1.2-6.8, it can be classified as highly soluble . The decrease in pH from 7.5 in the FDA guidances to 6.8 reflects the need to dissolve the drug before it reaches the mid-jejunum to ensure absorption from the gastrointestinal tract. 

The criteria for classification as a Class I API have been relaxed with respect to both the dose solubility ratio and permeability requirements. 

Please note that the doses used for the calculation of the dose solubility ratio are those stated in the EML. 

For multisource products containing BCS Class II APIs with dose solubility ratios of 250 ml or less, at pH 6.8, the excipients should also be critically evaluated in terms of type and amoimts of surfactants in the formulation. 

Solubility based on the lowest solubility in the pH range from 1 to 6.8 at 37 °C. Low indicates a dose solubility ratio > 250 ml for at least one pH value in this range. 

In a positive resist the image readout efficiency for a particular exposure dose is defined as the ratio of solubility rates ... 

Another aspect of dose that is often misimderstood is the influence of the solubility of a drug, which is often far too low (especially for lipophilic molecules) to allow sufficient drug to be absorbed in the time that it passes through the GI tract. A useful way to represent this is via the developability classification system (DCS) that explores the interplay between permeability, dose, and solubility [9]. Poor-solubility compounds (i.e., those with dose/solubility ratios greater than 1000) require more liquid than the GI tract has available, meaning that the only less soluble compounds that can be sufficiently absorbed are those with very high permeability (this is class Ila in the DCS system). The fact that brick dust is a common term in the medicinal chemist s lexicon is testament to the prevalence of this challenge. 

---