Dissolution rate polymorphs

In such cases, the Nogami method can be applied to the early points curve (Fig. 6) and the solubility, S, of the polymorph can be assessed. One of the important aspects of metastable polymorphs in pharmacy is exactly their higher solubility, since the dissolution rate will also be higher [Eq. (7)]. Hence the bioavailability will be increased where this is dissolution rate limited [21]. 

Selection of the most suitable chemical form of the active principle for a tablet, while not strictly within our terms of reference here, must be considered. For example, some chloramphenicol esters produce little clinical response [13], There is also a significant difference in the bioavailability of anhydrous and hydrated forms of ampicillin [14], Furthermore, different polymorphic forms, and even crystal habits, may have a pronounced influence on the bioavailability of some drugs due to the different dissolution rates they exhibit. Such changes can also give rise to manufacturing problems. Polymorphism is, of course, not restricted to active ingredients, as shown, for example, in an evaluation of the tableting characteristics of five forms or sorbitol [15]. 

Studies of polymorphs in recent years have pointed out the effects of polymorphism on solubility and, more specifically, on dissolution rates. The aspect of polymorphism that is of particular concern to the parenteral formulator is physical stability of the product [8]. Substances that form polymorphs must be evaluated so that the form used is stable in a particular solvent system. Physical stresses that occur during suspension manufacture may also give rise to changes in crystal form [9]. 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

The physical properties of the anhydrate form and two polymorphic monohydrates of niclosamide have been reported [61], The anhydrate form exhibited the highest solubility in water and the fastest intrinsic dissolution rate, while the two monohydrates exhibited significantly lower aqueous solubilities. In a subsequent study, the 1 1 solvates of niclosamide with methanol, diethyl ether, dimethyl sulfoxide, N,/V -dimethyl formamide, and tetrahydrofuran, and the 2 1 solvate with tetraethylene glycol, were studied [62], The relative stability of the different solvatomorphs was established using desolvation activation energies, solution calorimetry, and aqueous solubilities. It was found that although the nonaqueous solvates exhibited higher solubilities and dissolution rates, they were unstable in aqueous media and rapidly transformed to one of the monohydrates. 

Secondary processing does not always lead to phase transformations, as was shown during studies of the polymorphs of ranitidine hydrochloride [92]. No solid-solid transformation could be detected during either the grinding or compression of metastable Form I, stable Form II, or of a 1 1 mixture of these forms. The dissolution rates of both forms were found to be equivalent, and the solution-mediated transformation of Form I to Form II was observed to be slow. 

In the disc method, the powder is compressed by a punch in a die to produce a compacted disc, or tablet. The disc, with one face exposed, is then rotated at a constant speed without wobble in the dissolution medium. For this purpose the disc may be placed in a holder, such as the Wood et al. [Ill] apparatus, or may be left in the die [112]. The dissolution rate, dmldt, is determined as in a batch method, while the wetted surface area is simply the area of the disc exposed to the dissolution medium. The powder x-ray diffraction patterns of the solid after compaction and of the residual solid after dissolution should be compared with that of the original powder to test for possible phase changes during compaction or dissolution. Such phase changes would include polymorphism, solvate formation, or crystallization of an amorphous solid [113],... 

A very powerful method for the evaluation of solubility differences between polymorphs or solvates is that of intrinsic dissolution, which entails measurements of the rates of solution. One method for this work is to simply pour loose powder into a dissolution vessel, and to monitor the concentration of dissolved solute as a function of time. However, data obtained by this method are not readily interpretable unless they are corrected by factors relating to the surface area or particle size distribution of the powder. In the other approach, the material to be studied is filled into the cavity of a circular dissolution die, compressed until it exhibits the effective planar surface area of the circular disc, and then the dissolution rate is monitored off the surface of the rotating disc in the die [130],... 

Sulfathiazole has been found to crystallize in three distinct polymorphic forms, all of which are kinetically stable in the solid state but two of which are unstable in contact with water [130]. As evident in Fig. 20, the initial intrinsic dissolution rates are different, but as forms I and II convert into form III, the dissolved concentrations converge. Only the dissolution rate of form III was constant during the studies, indicating it to be the thermodynamically stable form at room temperature. Aqueous suspensions of forms I or II were all found to convert into form III over time, supporting the finding of the dissolution studies. Interestingly, around the melting points of the three polymorphs, form I exhibited... 

When drug polymorphs cannot interconvert as a result of being suspended in aqueous solution, a different bioavailability of the two forms usually results [126], For instance, the peak concentration of chloramphenicol in blood serum was found to be roughly proportional to the percentage of the B-polymorph of chloramphenicol palmitate present in a matrix of the A-polymorph [133]. The same concept has been found to apply to hydrate species, where the higher solubility and dissolution rate of the anhydrous phase relative to the trihydrate phase resulted in measurably higher blood levels when using the anhydrate as... 

In some instances, distinct polymorphic forms can be isolated that do not interconvert when suspended in a solvent system, but that also do not exhibit differences in intrinsic dissolution rates. One such example is enalapril maleate, which exists in two bioequivalent polymorphic forms of equal dissolution rate [139], and therefore of equal free energy. When solution calorimetry was used to study the system, it was found that the enthalpy difference between the two forms was very small. The difference in heats of solution of the two polymorphic forms obtained in methanol was found to be 0.51 kcal/mol, while the analogous difference obtained in acetone was 0.69 kcal/mol. These results obtained in two different solvent systems are probably equal to within experimental error. It may be concluded that the small difference in lattice enthalpies (AH) between the two forms is compensated by an almost equal and opposite small difference in the entropy term (-T AS), so that the difference in free energy (AG) is not sufficient to lead to observable differences in either dissolution rate or equilibrium solubility. The bioequivalence of the two polymorphs of enalapril maleate is therefore easily explained thermodynamically. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

The significance of polymorphism in the pharmaceutical industry lies in the fact that polymorphs can exhibit differential solubility, dissolution rate, chemical reactivity, melting point, chemical stability or bioavailability, among others. Such differences can have considerable impact on a drag s effectiveness. Usually, only one polymorph is stable at a given temperature, the others being metastable and evolving to the stable phase... 

It was mentioned that the solubility is that of the polymorph used to prepare the solid phase. It is possible to achieve higher dissolution rates by using unstable polymorphic forms of the compound. For example, if a hydrate is the stable polymorphic form in the presence of water, an anhydrous form would be more... 

The intrinsic dissolution rate method is most useful where the equilibrium method cannot be used. For example, when one wishes to examine the inLuence of crystal habit, solvates and hydrates, polymorphism, and crystal defects on apparent solubility, the intrinsic dissolution rate method will usually avoid the crystal transitions likely to occur in equilibrium methods. However, crystal transitions can still occur at the surface as in the case of anhydrous theophylline (De Smidt, 1986), where the anhydrous form converts to the hydrate and the intrinsic dissolution rate changes over time. In these cases, the application oflaer optical probe, which permits the detection of the drug concentration every few seconds, may prove to be very advantageous. 

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

There are numerous accounts in the literature of increased bioavailability in animals when changing the solid state. Kato and Kohetsu (1981) showed that form II amobarbital is more rapidly absorbedn vivo than form I. Dissolution rate experiments in water at(3"Showed a 1.6 times faster dissolution ratei vitro for form II compared to form I. Yokoyama et al. (1981) found that form III of 6-mercaptopurine was 1.5 times as bioavailable in rabbits as form I. It was six to seven times as soluble as the form I polymorph in studies by Kuroda et al. (1982). Kokubu et al. (1987) examined the therapeutic effect of different polymorphs of cimetidine in inhibition of ulcers in the rat. Pharmacokinetic studies found that form C was 1.4-1.5 times as bioavailable as forms A and B. This translated into a greater protection against stress ulceration, as shown in Table 19.4. The effec of form C was signiLcant compared to forms A, B, and D, which were all equivalent. 

The majority of characterized solvates are stoichiometric, with either water or organic solvents present in a Lxed ratio with the drug molecules. Glibenclamide was isolated as two nonsolvated polymorphs, a pentanol solvate, and a toluene solvate (Suleiman and Najib, 1989). Furosemide could form solvates with dimethylformamide or dioxane (Matsuda and Tatsumi, 1989). Haleblian and McCrone (1969) studied the solid forms of steroids, and found different dissolution rates for two monohydrates of Luprednisolone, a monoethanol and hemiacetone solvate of prednisolone and two monoethanolates and a hemichloroform solvate of hydrocortisone. Other solvents that have been reported to form solvates with drugs include methyl ethyl ketone, propanol, hexane, dimethylsulfoxide, acetonitrile, and pyridine. The potential toxicity concerns eliminate most of these from consideration as practical mechanisms of solubility enhancement for human therapeutics. 

There are many examples of drugs that show slower dissolution rates, lower solubilities, or less absorption in the hydrated form than the anhydrate. Stoltz et al. (1989) studied the dissolution rate of oxyphenbutazone powder in distilled water aftGTThe time to dissolve 50% of the powderwas only 0.75 min for the anhydrate and 22.9 min for the monohydrate. The IDR of the anhydrate was 1.63 times as fast as the monohydrate when compressed discs were used. Haleblian and McCrone (196S reported that the dissolution rate of pellets of Luprednisolone depended on the state of hydration of the drug. Thep-monohydrate dissolved 10% faster than thmonohydrate, but the anhydrate polymorph dissolution rates were 1.6 (form I), 1.4 (form III), or 1.3 times (form II) as fast as the a-monohydrate. 

Physical stability of the active ingredient is an important factor that should not be overlooked. The effect of polymorphism on properties of both the active ingredient (e.g., chemical stability, solubility, dissolution rate) and the drug product (e.g., bioavailability) have been extensively studied. Polymorphs or amorphous states of the active ingredient may impact chemical stability as well as dissolution rates, solubility, and bioavailability. This should be studied appropriately. This is discussed further in the sections below. 

An API is closely controlled in terms of crystal form, polymorph identity, particle size, impurity profile and content, solvent, and water levels. All of these quality parameters are defined in creating a drug product that has the desired pharmacological properties (e.g., tablet dissolution rate to give needed blood levels) and desired physical properties (e.g., stability and compatibility with drug delivery systems). 

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