Preparation of Resinates

The process for drug-resin complex manufacture is relatively simple. An ionizable active pharmaceutical ingredient (API) is loaded on to the resin by exchanging with the resin functional group's native ion, forming a drug-resin complex or "resinate" (also referred to as Polistirex in some literature). Drug structure (and biological activity) is not affected but bound drug is essentially inert and not "available" to the environment. Binding energy is determined by the ionic attractions between the resin functional group and the exchanging ions.

Drug may also be adsorbed on the resin surface in accordance with surface energy requirements [11]. Equation (8.1) describes the reaction of sodium sulpho-nate resin, R, being loading with a basic drug, X, of hydrochloride salt. Figure 8.2 illustrates the loading process and resulting resinate, IER-X.

The chemistry governing drug loading adheres to the Law of Mass Action requiring that drug be in concentrated solution to exchange onto the resin. The equilibrium reaction is expressed in (8.2) where, R is a resin and, D, is a drug, while X and Y are counter-ions.

Batch or column techniques can be employed for loading [12]. The batch technique in simple terms involves stirring a solution of the drug and suspended resin until equilibrium is reached. Column loading involves passing drug in solution through a column packed with resin until eluent and eluate concentrations are equal. The batch process is preferred for fine particles, whereas column operations are better suited for larger resin particles. Drug loaded resin is washed with deion-ized water to ensure that the native functional group ions and the drug's salt counter-ions are removed. Resinate is then dried to remove residual moisture.

R - SO3-Na+ + X • H+Cl- ^ R - SO3-H+ • X + Na+Cl

id id

Table 8.1 Commercially available ion exchange resins

Commercial name (compendial name)

Structure

Polymers

Amberlite™ IRP64 (polacrilex resin)

Table 8.1 Commercially available ion exchange resins

Commercial name (compendial name)

Structure

Polymers

Amberlite™ IRP69

H H H

H -1

Styrene/Divinylbenzene

(sodium polystyrene sulphonate USP)

S03" Na* |

H

H

H .

n

Purolite® ClOOCaMR

r H H H

H 1 I

Styrene/Divinylbenzene

(calcium polystyrene sulphonate BP/JP)

S03- Ca,/]

H I

H

H .

n

Methacrylic acid/ Divinylbenzene

Methacrylic acid/ Divinylbenzene

Ionizable Exchange group capacity Pharmaceutical uses

Strong acid 5 meq/g Reduce serum -S03" Na+ potassium

Strong acid 1.3-2 meq/g Reduce serum

-S03" Ca1/22+ potassium

Weak acid 10 meq/g Vitamin B12 and

-COO" H+ nicotine stabilization

Amberlite™ IRP88, Purolite® C115KMR (polacrilin potassium NF)

Duolite™ AP 143 (cholestyramine resin USP)

Methacrylic acid/ divinylbenzene

Styrene/Divinylbenzene

Methacrylic acid/ divinylbenzene

Styrene/Divinylbenzene

Weak acid 10 meq/kg Taste masking,

-COO" K+ P-lactam antibiotics

Strong base 1.8-2.2 g/g Reduce serum

-N+(R)3 CI" cholesterol

ON ON

Table 8.2 Ion exchange resin-containing pharmaceutical products

Trade name

Active Ingredient

Polymers

Indication

Dose

FDA approval

Renagel®

Selevamer

Allylamine and epichlorohydrin

Hyperphosphataemia

400 mg or 800 mg

1998

Paxil® oral

Paroxetine

Methacrylic acid and

Antidepressant

10 mg

1992

Suspension

divinylbenzene

Betoptic S® ionic

Betaxolol

Styrene and

Ocular hypertension

2.8 mg/ml

1989

Suspension

divinylbenzene

Tussionex®

Hydrocodone and

Styrene and

Antitussive and

10 mg and 8 mg

1987

12-hour

chlorpheniramine

divinylbenzene

decongestant

Nicorette®

Nicotine

Methacrylic acid and

Smoking cessation

2 mg or 4 mg

1984

Gum

divinylbenzene

Delsym®

Dextromethorphan

Styrene and

Antitussive

30 mg

1982

12-hour

divinylbenzene

Colestid®

Colestipol

Diethylenetriamine and epichlorohydrin

Hypercholesterolemia

5g

Fig. 8.2 Loading of basic drug onto cation exchange

Time, temperature and pH can affect drug loading. Maximum loading occurs when equilibrium is reached so longer loading times will generally promote greater drug loading. Increasing temperature usually improves drug solubility, leading to increased ionization of drug and possibly help loading of poorly ionized drug. Higher temperatures also reduce the activation energy and ease drug attachment. For weak cation exchange resins, neutral pH retards ionization and results in slower release rates [13]. The Henderson-Hasselbach relationship (8.3) predicts that, for a weakly acidic drug more than 50% of the drug species are ionized when solution pH is adjusted to greater than the drug's p^.

Conversely, (8.4) predicts that, for a weakly basic drug more than 50% is ionized when solution pH is less than the drug's p^a. If the solution pH is below (acidic drug) or above (basic drug) the drug's p^a the excess hydrogen and hydroxide ions will compete for binding sites on the resin and reduce loading efficiency.

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