Making A Hydrochloride Pharmaceutical Salt

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 an 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. Hydrochloride salts 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.

For one, 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 be used soon after it is formed. More often the gas is added to the free base dissolved in the lower alcohol.  HCl forms quite stable solutions in IPA which can be stored at ambient temperatures for several days.  Hydrochloric acid solutions can be made by in nonaqueous solvents adding acetyl chloride into ethanol where a quantitative reaction occurs to give hydrogen chloride and an equimolar amount of ethyl acetate.
 

For another, a recent patent, US2010/0204470A1, teaches the creation of hydrogen chloride in situ from trimethylsilyl chloride and any solvent with a silylable functionality or any inert solvent containing a slight excess over the silylchloride of a silylable group.

For another, 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 interest 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, a propanol, a butanol, acetone, 2-butanone, acetonitrile, etc..

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 salt but it will give evidence whether a solid salt exists 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 the hydrochloride of a pharmaceutical base has been formed but only a small amount, or no crystals at all, precipitate, three strategies are possible:

1. cool the solvent to decrease the overall solubility in the solvent volume
2. add an antisolvent which changes the quality of the solvent system and lowers the solubility
3. 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 temperature cooling should be applied and then an antisolvent 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 need for an in-process test to guarantee the proper solvent ratio. Additionally, second crops are more difficult to obtain from a mixed solvent without complicating your procedure.   Nevertheless, situations wherein a mixed solvent gives the best purification and recovery do occur.  It is an advantage if two solvents in such a case differ substantially in their boiling points. This allows the recovery of pure solvents from the filtrate. It is particularly advantageous if the better solvent for the substrate is the lower boiling solvent.

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