Solubility Enhancement

When and why should you engage in it?

By Dr. Ashok Patel

Solubility enhancement has been one of the most popular areas of research in drug delivery for past few decades. Both conventional techniques — particle size reduction, inclusion complexation, solid dispersions, salt formation etc. — as well as relatively newer techniques such as self-emulsifying systems, microemulsion, nanosizing and supercritical fluid processing have been tried and tested successfully, and the search for more advanced techniques rolls on. A significant requirement during early stage development, solubility enhancement also offers the possibility to reformulate approved drugs. Such high level of interest in this area can be attributed to the fact that it offers improvement in a key property of drug candidate, which has a direct impact on its bioavailability.

Researchers often selected poorly soluble drugs as models for techniques of solubility enhancement without giving due regards to their bioavailability. However, poor aqueous solubility won’t always lead to limited oral bioavailability. For example, Lorazepam, in spite of being practically insoluble (0.08mg/ml), has a good oral bioavailability1.

Oral bioavailability is determined by two major processes: dissolution (where solubility plays an important role) and absorption (governed by permeability). Dissolution is quite a complex phenomena and solubility is just one of the many factors that determines the dissolution of compound in GI tract. Apart from aqueous solubility, factors like dose and dosage form, pH solubility profile, contribution of bile salts and volume of medium available for dissolution play their part in determining whether dissolution is responsible for low oral bioavailability. Thus, one should consider all these factors rather than selecting a drug candidate for solubility enhancement merely on its solubility classification.

As referred by Oh D. M. et al.2-3, a dimensionless variable like dose number (D0) could be used as guidance for formulation scientist in selecting drug candidates. Many formulators are not aware about dose number and thus it is hardly considered during the development of formulation for solubility enhancement.

By definition, Dose number (D0) is the ratio of drug concentration in administered volume to the saturation solubility of drug.

D0 = (M0/V0)/Cs = (dose in mg/250ml)/solubility in mg/ml

Where M0= maximum dose; V0= 250 ml (considering 30-50ml as residual GI fluid together with 200-220ml, volume of a glass of water generally taken with a tablet or capsule).


For highly soluble drugs, dose number will always be less than unity and hence, we can assume that these candidates would never have solubility-limited bioavailability. Drugs that are slightly soluble (1-10mg/ml)4 and administered at low doses (250mg and less) will also fall in the safe zone, as far as low bioavailability due to solubility limitation is concerned. And as we go to the other two categories, very slightly soluble and practically insoluble drugs (0.1-1mg/ml and <0.1mg/ml respectively)4, dose becomes an important parameter that will determine whether there will be any solubility-limited bioavailability problems or not.

For these candidates, dissolution rate as well as pH solubility profile will have to be considered before assuming that solubility would limit their bioavailability. For example, take Aceclofenac, which is classified as practically insoluble and has a low oral bioavailability (60-70%)5. For calculation, if we use solubility value in distilled water (around 58µg/ml6) with a dose of 100mg, it would give you a dose number of 6.8, implying that low bioavailability is due to solubility limitations. However, the low bioavailability of Aceclofenac is often considered due to its first-pass metabolism7. Now considering its solubility (1.5mg/ml6) in intestinal pH (6.8) and recalculating the dose number, we get a number below unity, rightly suggesting that low bioavailability is not due to solubility limitation.

From this, it’s clear that simple consideration can lead to development in the right direction. Of course it’s a general statement but this calculation could serve as a starting point to screen the compounds that could benefit from solubility enhancement. For more complex analysis, we could introduce another dimensionless variable called Dissolution number (Dn)3, defined by the ratio of the GI residence time to the time taken for complete dissolution8. It could be understood from following equation:

Dn = [(π.R2. L)/Q] / [(ro2. ρ)/ (3.D.Cs)] = residence time/dissolution time

Where ro = the initial particle radius (µm); D = diffusion coefficient of the compound (cm2/sec); ρ = density of the compound (g/cm3); Cs = saturation solubility; Q = volume flow rate down the GI tract (cm3/min); R and L= intestinal radius and length respectively.

Compounds that gets dissolved completely during the transit through the intestine would have higher dissolution number (Dn > 1) and ideally a compound with Dn > 10, would get completely dissolve in 1/10th of the residence time and thus it could be assumed that dissolution rate enhancement of these drugs will never result in any improvement in the fraction of drug getting absorbed.

To show how dose number and dissolution number could be used together to get valuable information, we would have to know another variable called Absorption number (An)3, which is given by following equation:

An = (Peff. π. R. L)/Q

Where Peff = effective permeability coefficient (cm/s) and R, L and Q are as previously defined.

At An < 1, the drug would have a permeability-limited low bioavailability because a value less than one would mean that the transit rate is faster than the absorption rate.

Ideal drugs for oral administration would be ones with a low dose number (D0 10), and a high absorption number (An > 1). Most poorly soluble drugs would have a high An because of their lipophillic nature. In such cases, the amount of absorption and thus the bioavailability will either be dissolution rate limited or solubility limited or due to combination of both solubility/dissolution rate limited.

What follows are certain considerations that could be used to determine the rate-limiting factor responsible for low bioavailability:

1. At D0 > 10, bioavailability would be solubility limited and hence techniques that improves only the dissolution rate — like particle reduction — would not be ideal choices; surfactant solubilisation or chemical modification could be considered instead.

2. At dose number between 1-10, the limited bioavailability would be due to a combination of low solubility and dissolution rate. Techniques that work on improvement of both solubility and dissolution rate — like inclusion complexation or self-emulsifying systems — would be ideal for this category.

3. At dose number 1, the higher the dissolution number, the higher the absorption would be, so bioavailability would be mainly determined by dissolution rate. Micronization or nanosizing that increases the effective surface area could be used in this case.

4. Dose number and dissolution both at a value of 1 would lead to high variability in the absorption because at D0 = 1, a state of saturation is reached and Dn = 1 would mean that the residence time would become important, a physiological parameter that would likewise vary among the individuals.

5. At dose number less than 1, depending on the absorption number, dissolution rate enhancement could be applied for improving the absorption and bioavailability.

The decision to use of solubility enhancement for drug candidates should be made after a logical consideration taking into account the factors discussed above. For simple method for calculation of these parameters and further explanation on the model, readers are advised to follow our citations 3-8.


References

1Greenblatt, D.J., Shader, R.I., Franke, K., Maclaughlin, D.S., Harmatz, J.S., Allen, D., Werner, A., Woo, E. Pharmacokinetics and bioavailability of intravenous, intramuscular, and oral lorazepam in humans, Journal of Pharmaceutical Sciences, 68, 2006: 57-63.

2Oh,D.M., Sinko,P.J., Amidon,G.L. Predicting oral drug absorption in humans: A macroscopic mass balance approach for passive and carrier-mediated compounds. In D.Z. D’ Argenio (ed.) Advanced Methods of Pharmacokinetic and Pharmacodynamic Systems Analysis. Plenum Press, New York, 1991, pp. 3-11.

3Oh, D.M., Curl, R.L., Amidon, G.L. Estimating the fraction dose absorbed from suspensions of poorly soluble compounds in humans: A mathematical model. Pharm. Res. 10, 1993:264-270.

4The United States Pharmacopeia, 24th ed., by authority of the United States Pharmacopeial Convention, Inc., printed by National Publishing: Philadelphia, PA, 2000.

5Gonzalez, E., Cruz, C., Nicolas, R., Egido, J., Herrero-Beaumont, G. Long-term effects of nonsteroidal anti-inflammatory drugs on the production of cytokines and other inflammatory mediators by blood cells of patients with osteoarthritis. Agents Actions 41, 1994: 171-178.

6Tejal, S., Nagda, C ., Gandhi, T., Chotai, N.P. Development of discriminating method for dissolution of aceclofenac marketed formulations. Dissolution Technologies, 2008: 31-35.

7Shakeel, F., Faisal, M.S., Shafiq, S. Comparative pharmacokinetic profile of aceclofenac from oral and transdermal application. J Bioequiv. Availab. 1, 2009: 13-17.

8Rohrs, B.R. Biopharmaceutics modeling and the role of dose and formulation on oral exposure. In Borchardt, R.T., Kerns, E.H., Hageman, M.J., Thakker, D.R., Stevens, J.L. eds. Optimizing the “Drug Like” Properties of Leads in Drug Discovery. Springer New York, 2006, pp 153-166.

Ashok Patel is a freelance writer. He previously served as a research scientist, Pharma R&D, at Piramal Healthcare Limited. He can be reached at ashok2510@gmail.com