kilomentor

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

Specifying a three dimensional connectivity table for a chemical substance does not specify a single physical form of a substance. Such a uniquely bonded covalent molecular array will very often order itself in multiple ways in the solid state. This is often but not always related to different conformations (rotational isomers) any one of which can end up being the major conformer when the covalent substance is packed into a crystal lattice. Such different physical forms are called polymorphs if they have the same three dimensional connectivity and the same elemental analysis but different powder x-ray diffraction patterns.

Synthetic chemists from predominantly academic backgrounds, when they begin to regularly prepare organic substances in hundreds of grams or more, often see but do not recognize the significance of different physical properties for solids of the same structure. Most often these differences arise from different polymorphs that have crystallized in different crystal habits. Although these differences are not significant in terms of the success of a project as defined in synthetic terms, they are tremendously important in sao far as formulation difficulties are concerned, when the product is a pharmaceutical product.

Kilomentor vividly remembers such a situation in the first project he took into the plant. The first intermediate when produced on scale precipitated either as a smooth mud that took many hours to filter or (less often) as a coarse sandy material that seemed to filter in minutes. Although which one was obtained in the laboratory was of minor importance, the plant operators you can imagine had a strong preference!

It was once thought that the melting point of a solid was 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 forms of the same basic molecular structure can have different melting points. Very often however when a melting point is being determined by watching the behaviour of a solid in a melting point tube, two polymorphs will appear to have the same melting point when they actually do not, because the lower melting form may t convert to the higher melting form, without the observer detecting it, during the melting point determination. Or sometimes the two polymorphs may have different melting points but which are very close to each other.

Crystal Habits

If two samples have the same three dimensional covalently bonded array and the same powder x-ray diffraction (XRD) pattern and the same elemental analysis, but look different; then, at the unit cell scale the two substances are the same but they are said to have different crystal habits. Crystal habits are characterized by the relative dimensions of the macroscopic crystal forms. For example, a substance may crystallize as needles (essentially in a one dimensional line), plates (in a two dimensional plane), or as three dimensional rombahedra. A crystal habit difference occurs when two or more faces of the same crystal class grow at different relative rates. This is a macroscopic difference in relative dimensions not just the difference between large and small crystals of the same overall shape (ie large and small needles).

It is a well known teaching from inorganic gravimetric analysis that if a solid is too fine to allow rapid quantitative filtering 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 there is the teaching:

“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 super-saturation, solvent type and polarity, water content, the type and concentration of impurities (particularly structurally related impurities), solute concentration and the solution viscosity all can change crystal habit. Further complicating the crystallization operation, many of these factors vary 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 powder flow can be addressed by forming the powder into lumps (called granulation) or by pressing, 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 modify differently 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 any crystal nucleation an otherwise solid product remains a troublesome 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 alternately raising and lowering the temperature or having different parts of the oil at different temperatures and/or stirring and scratching with a glass rod to create discontinuities on the vessel’s wall where nucleation has a better chance to begin.

Hydrates and other Solvates

Two or more chemical substances can also crystallize together in an organized relationship within the crystal lattice as co-crystals. This is much more common than is commonly realized because all racemic compounds are co-crystals of the two enantiomeric (mirror image) forms. Co-crystals wherein one of the chemical species is a volatile substance are called solvates. Hydrates are just a special subclass of solvates where the solvent is water.

A synthetic process chemist who prepares a three dimensional covalent structure different from the target structure has failed in the project. If the skeleton and stereochemistry are correct the synthetic organic process chemist has succeeded no matter what polymorph, solvate or hydrate is recovered from the final synthetic step. This is because polymorphs are routinely and simply interconverted and solvates and hydrates are readily desolvated. In the case of solvates or hydrates this is usually done by some combination of vacuum, heat and chemical reaction either alone or severally. The use of dehydrating agents is one 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 or 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, is the most prescribed medicine in the world; there are 23 known polymorphic forms, most 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 sometimes actually 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. A case is known where a polymorph is claimed 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, although poor flow as has already been noted can be changed by mechanical processing.

In summary there are, in a minority of instances, significant advantages to using a particular polymorph in a pharmaceutical product, but usually the claims to their importance are really about monopoly patent rights. Moreover, discovering polymorphs does not require ingenuity or inventiveness. The literature contains loads of suggestions for simple crystallization conditions that can give rise to polymorphs. It has been said that the number of polymorphs of a pure substance is probably directly proportional to the time spent looking for them. There are even automated robotic systems that can be used to search for polymorphs. No wonder that scientists that author polymorph patents don’t subsequently publish their work in peer journals. It’s not creative, not surprising and not unusual. It’s not work you can expect admiration for doing.

Getting crystals to consistently form with a chunky crystal habit on the other hand might require some if the solid did not give you what you want simply by old fashioned digestion. Avoiding needles and plate morphologies really can help to avoid demixing of the powder mixture of active pharmaceutical and the inactive excipients when it is flowing into the punches of a tablet press. The problem here is that the problem can also be overcome most of the time by granulating (lumping) components or conversely by grinding chopping and sieving them.

Solvates are discovered auromatically during the search for polymorphs. all one needs is a proper characterization of the solid that is isolated. A thermogravimetric analysis, an NMR, a n elemental analysis and a weight loss on drying. That is just careful classical measurement of properties.

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