Prediction of Drug Solubility in Adhesive Matrix for ... - ACS Publications

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Chapter 12

Prediction of Drug Solubility in Adhesive Matrix for Transdermal Drug Delivery Based on a Solvation Parameter Model Jianwei

*

Li and Jeremy J. Masso

Transdermal Drug Delivery, 3M Drug Delivery Systems, 3M Center, Building 260-3A-05, St. Paul, M N 55144 Corresponding author: [email protected] *

The work presented here establishes the relationship between drug solubility in two acrylate adhesives with a previously defined drug-polymer interaction parameter and drug solubility in acetonitrile. The drug solvation parameter model decomposes a hard-to-measure quantity into two easily measurable parameters. It is concluded that there is an excellent linear relationship for the parameters involved. Thus, the model can be used to compute the solubility in the polymer for new drug candidates. Moreover, the two parameters in the relationship can be either easily measured or computed based on their molecular properties by the solvation parameter model. The methodologies presented can be applied to other adhesives.

186

© 2006 American Chemical Society

In Polymeric Drug Delivery II; Svenson, Sönke; ACS Symposium Series; American Chemical Society: Washington, DC, 2006.

187


Introduction One of the critical parameters in the optimization of drug-in-adhesive (DIA) transdermal formulations is drug solubility within the adhesive. The desired solubility not only provides optimal permeation flux of the drug but also meets the therapeutic dose requirement (e.g., mg per day) within a reasonable patch size (1,2). Although it is a critical parameter, there is no easy quantitative measurement method available for the purpose of formulation study due to the complexity of the adhesive matrix. Perhaps two of the most commonly used methods are accelerated crystal seeding and differential scanning calorimetry (DSC) (3,4). The first method is essentially qualitative, while DSC is the method of choice i f a quantitative study is performed. Both experiments, how ever, are time-consuming and require significant optimization. Accordingly, a quick methodology to estimate the drug solubility in a polymer matrix for trans dermal drug delivery is highly desirable. It should be noted that either polymer or adhesive is used interchangeably to refer to the polymers used in transdermal formulations. Several requirements have to be satisfied for the development of a reliable methodology. First, a theoretical basis is required relating drug solubility to predictable parameters that can be connected to the properties of the drug (and adhesive) by quantitative structure-property relationships (QSPR) (5). Second, a quantitative method is needed to measure drug solubility within the adhesive. The D S C technique is adopted in this study because it is quantitative and relatively easy to perform. Furthermore, it has been widely used to characterize drug formulations and to study drug-excipient interaction or compatibility (6-9). Third, model drugs have to be carefully selected for calibration of the theoretical relationship, covering a wide range of drug properties. A novel approach to the characterization of drug-polymer interactions has been described previously (10). In this approach, a dry adhesive is allowed to swell in dilute acetonitrile (ACN) solutions of probe compounds. After the swelling, the dissolved drugs can interact with polymer fragments or monomer functional groups, resulting in a decrease in the drug concentration due to sorption. The sorbed amount of molecules is an indication of the strength of the interaction of each compound with the polymer relative to A C N , and can be considered as an interaction parameter. This parameter is the basis of the current study. As will be shown in the theoretical section, drug solubility within an adhesive can be thermodynamically decomposed (linearly) into the interaction parameter and the drug solubility in A C N . Both parameters have been shown in previous studies to correlate well with molecular properties (or descriptors) of the drug molecule by the solvation parameter model. In other words, the two simple parameters can be computed based on these molecular properties. Thus,



188

if we can "calibrate" the thermodynamic relationship (eq 5) with model drugs or compounds to determine the model coefficients for an adhesive, this relationship, combined with the calculation of interaction parameter and drug solubility in A C N , can be used to predict the solubility within the adhesive for a new drug candidate. This study is intended to validate and establish the relationships between drug solubility in two acrylate adhesives with the drug-polymer interaction parameter and drug solubility in A C N . A series of reference compounds or drugs is selected, and their solubility values in adhesives are measured by D S C technique. The data are then used to establish the relationships for the estimation of the solubility of new drug candidates.

Theoretical Consideration The Solvation Parameter Model The solvation parameter model is a type of general quantitative structureactivity relationship. It relates the physical properties to several types of intermolecular interactions (dispersion, polar, hydrogen bond association, and hydro phobic interactions) (11-12). A good example is the drug solubility (S ) in water (13): w

Log(S ) = c + eE + sS + aA + bB + vV + gAB w

(1)

where c is the regression constant; E, S, A , B , and V are called solute or drug descriptors, representing their physicochemical properties; and e, s, a, b, v, and g are the coefficients. The descriptors are the excess molar refraction (E); dipolarity/polarizability (S); "overall" or "effective" hydrogen bond acidity (A) and basicity (B); and McGowan characteristic molar volume (V) (12). Equation 1 contains five product terms representing the properties (descriptors) of the drug molecules and the system (solvent) (a g A B term is used to describe solute-solute interactions, and usually absent in the model). The econstant is the capacity of water to interact with the drug molecules through n or n electron pairs. The s-constant is the capacity of water to take part in dipoledipole and dipole-induced dipole interactions. The a-constant is a measure of the hydrogen-bonding (HB) basicity of water, and the b-constant is a measure of its H B acidity. Finally, the v-constant is a measure of the ease of cavity formation in water. Similar equations have been obtained for retention in chromatography, octanol-water partition coefficient, skin permeation coefficient, etc. (12,14).


189 Molecular descriptors are available for more than 4000 compounds, and further values can be obtained by parameter estimates or experiment. (15) A software package (Absolv) is available to calculate molecular properties (Sirius Analytical Instruments Ltd., East Sussex, U K ) .


Physicochemical Characterization ofAdhesives We have reported a methodology to characterize the physicochemical properties of an adhesive that are directly related to transdermal drug delivery (10). A set of acetonitrile solutions of judiciously selected probe compounds with known physicochemical properties was brought in contact with a dry adhesive. After swelling of the adhesive, interactions of solutes with swollen polymer will occur. The strength of these interactions is indicated by the sorbed amount of molecules {Sn) onto the polymer (proportional to binding constant), and related to the properties of the solutes. As a result, the sorbed amount of probe molecules can be described by an equation similar to eq 1:

The sorbed amount is a result of differential interactions between the solute (drug) and both, the polymer and A C N (both regarded as solvent), through the intermolecular interactions described above. The system constants in eq 2 are defined by the complementary (differential) interactions of both adhesive and A C N with the descriptors, and contain rich information of the properties of the polymer. The e-constant is a measure of the difference in system polarizability (or the capacity of the polymer relative to A C N to interact with the probe mole cules through n or n electron pairs). The s-constant is a measure of the difference in system dipolarity/polarizability (or the capacity of the polymer relative to A C N to take part in dipole-dipole and dipole-induced dipole interactions). The a-constant is a measure of the difference in H B basicity of the polymer relative to A C N , and the b-constant is a measure of the difference of H B acidity of the polymer relative to A C N . Finally, the v-constant is a measure of system hydrophobicity of the polymer relative to A C N (or relative ease of forming a cavity for the probe in the polymer relative to A C N ) . A C N is a polar solvent, and essentially does not possess H B capability. The coefficients in eq 2 will mainly reflect the relative polar and absolute H B properties of the adhesive 00).

Finally, the relationship between the sorbed amount and physicochemical properties of the probe compound can be regarded as a valuable model to predict


190 the sorbed amount for a new drug entity. This sorbed amount was defined as a drug-polymer interaction parameter or index, as mentioned earlier.

Drug-Polymer Interactions As stated, Sn is proportional to the binding constant with the swollen


adhesive.

Therefore, Lntfin) is the difference in interaction (energy) of drug

molecules with the adhesive relative to A C N (16): Lnf$n)= E _ Dmg

where E _ Drug

and E _

Adhesive

Dnig

Adhesive

- E _ Drug

(3)

ACN

denote the drug-adhesive and drug-ACN

ACN

interaction energy, respectively. It is then derived from eq 3 that the degree of drug-polymer interactions can be related to £w(

Prediction of Drug Solubility in Adhesive Matrix for ... - ACS Publications

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