Making the Hydrochloride Pharmaceutical Salt of Basic Drug Substances

kilomentor | 21 April, 2008 18:37

By far the most frequently successful pharmaceutical salt is the hydrochloride. In fact the hydrochloride salt is selected 50% of the time when chemists look for an acceptable salt. Typically, there must be a very good reason for not adopting this salt. If a hydrochloride crystallizes, one typically needs a n excellent reason not to use the hydrochloride.

The hydrochloride is a preferred choice because chloride does not have any activity of its own, unlike bromide, nitrate and others. Hydrochloric acid is a very significant acid in the stomach. By salt exchange hydrochlorides are formed to some extent no matter what the counter ion of an API is in the pharmaceutical product.

Hydrochloric acid is a strong mineral acid strong enough to quantitatively protonate even weak bases.

Hydrochlorides characteristically are substantially more soluble than the free bases used to make them, so the hydrochloride typically improves the bioavailability.

Hydrochlorides can be prepared in aqueous solution, in protic organic solvents, in aprotic organic solvents, and in non-polar solvents because hydrogen chloride can exist in both a covalent form in apolar solvents or as ionized protons and chloride ions in more polar solvents. The actual acidity varies being equal to the acidity of the conjugate acid of the solvent molecule. That is to say hydronium ions exist in water, protonated alcohol ions in alcohol, protonated acetic acid in glacial acetic acid or protonated ethyl acetate molecules in ethyl acetate. The multiple forms of HCl result in multiple techniques for the addition of the hydrogen and chloride ions to the pharmaceutical base we need to make into a salt.

Hydrogen chloride gas can be passed into neat organic solvents to prepare titratable molar solutions that are quite stable. Hydrogen chloride in lower alcohols is not stable for a long time and must e used soon after it is formed. More often the gas is added to the base dissolved in the lower alcohol. HCl forms quite stable solutions in IPA which can be sotred at ambient temperatures for several days. Hydrochloric acid solutions in non aqueous solution can be made by adding acetyl chloride into ethanol wher a quantitative reaction occurs to give hydrogen chloride and an equamolar amount of ethyl acetate.

A recent PCTpatent teaches the creation of hydrogen chloride in situ from trimethylsilyl chloride and any solvent with a silylated functionality or any inert solvent containing a slight excess over the silyl chloride of a silylable group.

Hydrochlorides can be made by reaction of the organic base with an equivalent of ammonium chloride. The stronger organic base preferentially takes the hydrogen chloride and the ammonia gas is liberated and may exit the reaction mixture.

If the free base of concern has some solubility in water, the hydrochloride can be made from aqueous hydrochloric acid and the base in water. Often heating is required to get the free base dissolved and the hydrochloride salt separates on cooling. In aqueous solution the solubility of the amine hydrochloride can be decreased by the addition of additional inorganic water soluble chloride to increase the common chloride ion. The addition of inorganic salts also increases the precipitation by the salting out effect.Excess hydrochloric acid can be used to decrease the solubility of the desired salt so long as the pharmaceutical chloride is stable in strong aqueous acid.

Standard aqueous solutions of hydrochloric acid can be added directly into the base dissolved in a water miscible polar solvent such as methanol, ethanol, propanols, butanols, acetone, 2-butanone, acetonitrile,

The most powerful and widely practiced method of making a hydrochloride salt in the laboratory is to add gaseous hydrogen chloride into a diethyl ether solution of the free base. If you think a hydrochloride salt might not be crystalline, this technique is likely to provide evidence one way or the other. It is not a practical process method to make the slat but it will give evidence that the solid salt is possible and will provide some seed crystals for other preparative methods.

If a solid pharmaceutical hydrochloride is formed, the next goal is to obtain it in a satisfactory recovery. Pharmaceutical bases are typically expensive moieties and losing material in a low recovery hydrochloride formation is undesirable. When a solution of a hydrochloride and the pharmaceutical base has been formed but only a small amount or no crystals at all precipitate three strategies are possible

cool the solvent to decrease the overall solubility in the solvent volume
all an antisolvent which changes the quality of the solvent system and lowers the solubility
add an antisolvent and then cool

As a rule of thumb if the recovery is 80% or more at ambient temperature, simply cooling the solvent can be expected to give an excellent recovery; if the recovery is 40-80% at ambient cooling should be applied and then an altisolvent judiciously added; but when the starting recovery is less than 40% an antisolvent should be added to just the cloud point and then cooling should be applied.

Treatment is completely reversible. What you cool down you can rewarm so this is usually tried first.

If treatment 2 is used it is useful for the analysis of the results to take a sample of the solid obtained just by cooling in order to measure the purity at that point, then add the antisolvent to give a practical recovery and compare the purity of the product when using an anti-solvent with the purity before that addition.

When the solid formation in the single solvent condition is low or none, an anti-solvent is added to the cloud point either to a hot or ambient solution and then controlled cooling is applied to try for crystallization.

Mixtures of solvents are not preferred in scale up processes because it introduces the nedd for an in process test to guarantee the proper solvent ratio. Second crops are more difficult to obtain from a mixed solvent in a simple procedure. Nevertheless situations where a mixed solvent gives the best purification and recovery do occur. It is advantage if two solvents differ substantially in boiling point. This allows recovery of pure solvents from the filtrate.

Solvents that form an azeotrope with water have the advantage that it is easier to be sure that the crystallization is under anhydrous conditions.

Hydrochlorides of high molecular weight secondary and tertiary amine bases can be extracted into halogenated solvents such as methylene chloride, chloroform or 1,2-dichloroethane and evaporation of these solutions of solvent switching to a non-halogenated solvent can recover the product.

Bulky secondary amines, which are difficult to extract in this way frequently can be extracted so long as the amount of both the aqueous and organic phase is kept small so that the concentration of the solute is high. This is effective because secondary amines with at least one hydrogen are more likely to form dimers in the organic phase increasing the apparent extraction coefficient.

Note:Kilomentor Consulting

Although the purpose of the Kilomentor Blog is chemical process development education emphasizing organic and pharmaceutical synthesis so that you can create your own solutions, Kilomentor will help with particular problems. E-mail slemon.khomasurya@sympatico.ca or kilomentor@sympatico.ca. is available for can participate in training