Polymorphism in Organic Syntheses

Keywords: polymorphs, polymorphism, solvates, hydrates, crystal habits, digestion, flowability, powder mixing, dissolution, solubility, bioavailability, API

The specification of a particular three dimensional connectivity table for a chemical substance does not produce a single physical form of the substance.  A uniquely covalently bonded molecular array very often orders itself in multiple ways in the solid state. This is often, but not always, related to different conformations (rotational isomers) that can be the major conformer when the covalent substance is packed into the crystal lattice.  Two such different physical forms are called polymorphs if the two have the same elemental analysis but different powder x-ray diffraction patterns. 

Synthetic chemists from predominantly academic backgrounds, when they begin to prepare organic substances in 100s of grams or more, often see but do not recognize the significance of different qualities of the same solid.  Most often these differences come from different polymorphs that may have also crystallized in different crystal habits.  Although these differences are not significant in synthetic terms, for  the success of a project they are tremendously important with respect to formulation difficulties, if the product is a pharmaceutical final product.

Kilomentor vividly remembers the first project he took into the plant.  The first intermediate, when produced on scale, either precipitated as a finely divided mud that took many hours to filter or less often as a material with the consistency of course sand that seemed to filter in minutes.  Although it was of minor importance in the laboratory, the plant operators had a strong preference.

Crystal Habits

If two substances have the same three dimensional covalently bonded array, have the same powder x-ray diffraction pattern and the same elemental analysis, but look different, then the two substances are at the unit cell scale the same but have what is called different crystal habits.  Crystal habits are distinguished by the average relative dimensions of the macroscopic crystal forms.  For example, a substance may crystallize as needles, plates, or rhombs.  A crystal habit difference occurs when two or more faces of the crystal grow at different relative rates. 

It is an elementary teaching from inorganic gravimetric analysis that if a solid is too fine to allow rapid quantitative filtering in high purity, this condition can often be improved by what is called digestion.

For example, in a Textbook of Quantitative Inorganic Analysis including Instrumental Analysis, Arthur I. Vogel, Third Edition, John Wiley and Sons, New York. N.Y. 1961, at page 111-112 it is taught:

“This [digestion] is usually carried out by allowing the precipitate to stand for 12-24 hours at room temperature, or sometimes by warming the precipitate for some time, in contact with the liquid from which it was formed: the object is, of course, to obtain complete precipitation in a form which can easily be filtered. During the process of digestion or the ageing of precipitates, at least two changes occur. The very small particles, which have a greater solubility than the larger ones, will, after precipitation has occurred, tend to pass into solution, and will ultimately redeposit on the larger particles; co-precipitation on the minute particles is thus eliminated and the total co-precipitation on the ultimate precipitate reduced.  The rapidly formed crystals are probably of irregular shape and possess a comparatively large surface; upon digestion these tend to become more regular in character and also more dense, thus leading to a decrease in the area of surface and a consequent reduction of adsorbtion.  The net result of digestion is usually to reduce the extent of co-precipitation and to increase the size of the particles, rendering filtration easier”.

It is well known that pronounced variations in the crystallization conditions: temperature, rate of temperature change, intensity of stirring, the initial level of supersaturation, solvent type and polarity, water content, type and concentration of impurities (particularly structurally related impurities) concentration and the solution viscosity affect crystal habit. Further complicating the operation, many of these factors change as the crystallization proceeds.  Crystal habits probably will not affect solubility, dissolution rate or bioavailability. Crystal habits can be important for the flow properties of powder mixtures, but as skilled practitioners know, problems in this area can be addressed by granulation of the active or by grinding, micronizing or other well known mechanical aggregation or disintegration methods. 

The core factors that affect crystal habit also affect the crystal size because they cause different variations in the rates of crystal nucleation and crystal growth.  Synthetic chemists typically are most experienced in the wide variety of conditions that may promote crystal nucleation because without crystal nucleation a product is most likely to give an undesirable oil.  The optimal crystal nucleation temperature is rarely the best temperature to increase the rate of crystal growth. That is why on laboratory scale, crystallization is often promoted by alternate raising and lowering the temperature, having different parts of the oil at different temperatures, or by stirring and scratching with a glass rod to create discontinuities on the vessel’s walls, where nucleation can begin.

Two or more chemical substances can also crystallize together in an organized relationship within the crystal lattice.  This is much more common than is realized because all racemic compounds are co-crystals of the two enantiomeric forms.  Co-crystals when one of the chemical species is a relatively volatile substance are called solvates of the non solvent moiety.  Co-crystals in which the solvent in the solvate is water are called hydrates of the non-volatile constituent.

It was once thought that the melting point of a solid is an invariant characteristic of a particular covalent atomic arrangement (molecular structure) but the existence of polymorphic forms shows that this is not true.  Different polymorphic can have different melting points.  Very often however when a melting point is being determined by visual observation, two polymorphs will appear to have the same melting point when they actually do not because the lower melting form may be converting, unobserved, to the higher melting form during the melting point determination or the two polymorphs may have different melting points which are very close to each other.

A synthetic process chemist who prepares a three dimensional covalent structure different from the target structure has failed in the project.  The synthetic organic process chemist has succeeded however no matter what polymorph, solvate or hydrate is recovered from the final synthetic step. This is because polymorphs are regularly and simply interconverted and solvates and hydrates are typically readily desolvated, usually by some combination of vacuum, heat and chemical reaction of the solvating substance. The use of dehydrating agents is a common example of this.

Although polymorphs, solvates and hydrates are rather unimportant to the synthetic chemist, they are very important to formulators who work to make pharmaceutical dosage forms like tablets, powders or capsules and to patent chemists who try to create intellectual property that provides a legal monopoly for pharmaceutical companies.  Although polymorphs can be found by applying routine screening strategies, patenting these new polymorphs of medicinally importance compounds can extend the legal monopolies of the ‘inventors’ by a dozen years or more.  The anti-cholesterol drug, atorvastatin, first discovered by Pfizer, was the most prescribed medicine in the world and there are 23 known polymorphic forms,  most or all of which have been patented.

Although the greatest importance of polymorphs is that they can be used to extend pharmaceutical patent monopolies, the differences between polymorphs, hydrates and other pharmaceutically acceptable solvates can be important when these forms are incorporated with excipients into a drug product such as a tablet or capsule.  One crystalline polymorph might formulate to produce a stable suspension while another might deteriorate on storage.  One polymorph has been known to have up to ten times the absolute solubility of another and this can affect the bioavailability. Different polymorphs have different tendencies to retain solvent and this can be important for the removal of impurities during the washing of a crystalline API.  Different polymorphs of a particular pharmaceutical can have different tendencies to be created in different crystal habits and crystal habit and crystal size are key determinants of the flow properties and manufacturability of API in solid powder mixtures.