MXPA97003304A - Procedure to select a salt to prepare an inclus complex - Google Patents

Abstract

A method for locating one or more salts of a compound, said salts having a solubility of a cyclodextrin equal to or greater than an objective solubility of a cyclodextrin equal to or greater than a desired objective solubility, including obtaining a series of salts of said compound, measure the solubility in the equilibrium of each salt of said series in the mentioned cyclodextrin and compare each measured solubility with said objective solubility.

Description

PROCFPIGITENTO? F SFI EC ION DF UNQ SQL PQRQ PREPQRQR AN INCLUSION COMPLEX CfflPQ. PE Lfl INVENTION This invention relates to a method of selecting a salt of a medicinal compound for use in the preparation of a composition of matter comprising said salt and a cyclodextrin. Specifically, it relates to a process for locating salts that are very soluble in aqueous solution of cyclodextrin.

COMPONENT OF THE INVENTION The formulation of pharmaceutical dosage forms is often hampered by poor solubility in water and / or stability of the drug of interest, which in turn can severely limit its therapeutic application, conversely, an increase in solubility and Stability of the drug by a suitable formulation can therefore lead to an increase in the therapeutic efficacy of the drug. Various methods have been used to increase the solubility and stability of drugs such as the use of organic solvents, emulsions, liposomes and micelles, adjustments to the pH and dielectric constant of the solvent systems of the formulations, chemical modi ications and training. of drug complexes with suitable complexing agents such as cyclodextrins. Cyclodextrins, sometimes referred to as Schardinger dextrins, were first isolated by villiers in 1891 as deferred from Bacillus amvlQbacter of potato starch. Lae bases of the chemistry of cyclodextrins were established by Schardinger in the period 1903-1911. However, until 1970, only small amounts of cyclodextrins could be produced in the laboratory and the high production cost prevented the use of cyclodextrins in the industry. In recent years spectacular improvements in the production and purification of cyclodextrins have been achieved and these have become much cheaper, thus making possible the industrial application of cyclodextrins. Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on the outer surface and an empty cavity at the center. Their outer surface is hydrophilic, and therefore they are normally soluble in water, but the cavity has a lipophilic character. The most common cyclodextrins are a-cyclodextrin, β-cyclodextrin and t-cyclodextrin, respectively formed by 5. 7 and 8 units of glucose bound o-1,4. The number of these units determines the size of the cavity. Lae cyclodextrins are capable of forming inclusion complexes with a wide variety of hydrophobic molecules by picking up an entire molecule, or some part of it, in the empty cavity. The stability of the complex formed depends on how well the host molecule fits in the cyclodextrin cavity. Common cyclodextrin derivatives are formed by alkylation (for example, methyl- and ethyl-β-cyclodextrin) or hydroxyalkylation of the hydroxyl-derivatives of the α-, β- and t-cyclodextrin, or by substituting the groups primary hydroxyl with saccharides (eg, glucosyl- and β-altosyl-β-cyclodextrin). Hydroxypropyl-β-cyclodextrin and its preparation by the addition of propylene oxide to β-cyclodextrin and hydroxyethyl-β-cyclodextrin and its preparation by the addition of ethylene oxide to β-cyclodextrin were described in a Gramera et al. (US Patent No. 3,459,731, issued in August 1959) more than twenty years ago. Although cyclodextrins have been employed to increase the solubility, dissolution rate and / or stability of a large number of compounds, it is also known that there are many drugs with or without the formation of a complex with cyclodextrin or not. offers advantages See 2. Szejtli, Cyclodextrins in Drug Formulations: Part II, Pharmaceutical Technology, 24-38, August 1991 When the formation of a salt is feasible, many medicinal compounds are administered in the form of one or other of their pharmaceutically acceptable salts. Nevertheless, not all of them are freely soluble in aqueous medium and therefore the formation of a complex of the salt of interes with a cyclodextrin is frequently explored as a means to increase the solubility of the salt in water. It is a common belief that a salt of a drug dissolves in an aqueous medium containing cyclodextrin simply by dissociating to form a charged drug molecule and its counter ion, and that the molecule of dissociated (ie charged) molecule is the host molecule that forms the inclusion complex with the ciclodextpna. A consequence of this is the belief that there is no difference in solubility in the balance between the salts of a given drug in a particular cyclodextrin, if a phase diagram of solubility of a particular drug is constructed in a particular aqueous cyclodextrin. (ie, a representation of the solubility in the maximum equilibrium of a salt of a drug in the aqueous cyclodextrin as a function of the concentration of cyclodextrin), the slopes of the straights represented by different salts of the drug should be the same. BRIEF DESCRIPTION OF THE INVENTION This invention provides a method of selecting, choosing or locating one or more salts of a compound, said salts having a solubility in a cyclodextrm equal to or greater than a desired objective solubility, which consists of obtaining a series of salts of said compound, measuring the solubility in the equilibrium of each salt of said series in one. aqueous solution of said cyclodextrin and comparing each measured solubility with the stated objective solubility. That salt or salts having a solubility balance greater than the desired target solubility are therefore chosen as the salt or salts desired. Those familiar with the use of cyclodextrins will understand that the invention is applicable to any medicinal compound that forms salts, that forms a complex with an extrinsic cycle and that has poor aqueous solubility. In a similar aspect, this invention provides a method of determining a useful salt, from a series of salts of a particular medicinal compound, for use in the preparation of a composition of matter comprising said salt and a cyclodextrin, consisting of said procedure in: a. obtain said series of salts, - b. determining the solubility in the equilibrium, in aqueous solution of cyclodextrin, of each of said salts of said one; and c. selecting, as the above-mentioned useful salt, a salt of said series has a solubility in said cyclodextrin solution equal to or greater than the desired objective solubility. The invention further provides a composition of matter formed by a pharmaceutically acceptable salt of a medicinal compound and a cyclodextrin, said salt having been located or selected by the above methods. In a preferred embodiment, the composition is an inclusion complex of a complex salt of a cyclodextrin. The phrase "composition of matter" as used herein comprises, inter alia, compositions of a medicinal compound and a cyclodex pna which are dry physical mixtures, which are dry inclusion complexes and which are aqueous solutions of dissolved inclusion complexes. . For example, the composition can be formed by a dry mixture of a medicinal compound physically mixed with a dry cyclodextrin. The composition, is a preferred embodiment, may also be formed by an aqueous solution that has been lyophilized or otherwise removed, for example in a vacuum oven or other suitable instrument, such that the composition comprises an inclusion complex ( pre-formed) of complex cyclodextrin-co, which can be reconstituted subsequently. The composition can also be formed by the same solution, that is, a medicinal compound cyclodextrin plus water. The inclusion complexes are within the scope of the term "composition of matter" whether they are pre-stressed, formed insitu or formed in vivo. In a more specific embodiment, this invention provides a method of determining a useful salt, from a series of salts of a particular medicinal compound, for use in the preparation of a composition of matter comprising an inclusion complex of said salt in a triple cycle, said procedure consisting of: a. determining or selecting an amount of said medicinal compound required for therapeutic efficacy; b. determining or selecting a maximum total dose to the one administering said quantity of medicinal compound; c. calculating the minimum required solubility of a salt said said compound needed to formulate the maximum total dose cited; d. obtain the series of salts cited; and. determining the solubility in the equilibrium of each of said salts in said cyclodextrin; and f. selecting, as the above-mentioned useful salt, a salt of the aforementioned series having a solubility in said cyclodextrin sufficient to allow preparing a total dose equal to or less than the maximum total dose quoted. The previous reference to a "series of salts" of a compound means that, of course, the compound must be able to form salts. Furthermore, the term "a series of salts of a particular medicinal compound" means two or more different salts of a particular medicinal compound. The series can be formed as a group and analyzed "in parallel" to determine if any of the salts is useful for preparing a useful salt / cyclodextrin composition, or each component of the group can be analyzed separately, for example at different times and in different places. The series of salts can be "obtained" in any way, for example by preparing them or ordering them prefabricated from a commercial supplier. The term "salt" usually means a pharmaceutically acceptable salt. The salt may be anhydrous or in the form of one or more solvates, such as hydrates, including mixtures thereof. The salts could be given in different polymorphic forms. A "desired objective solubility" as used herein may be a minimum, usually predetermined or preselected, solubility required for the compound being analyzed. The minimum solubility required will generally be selected based on the therapeutic need. For example, suppose that it is desired to administer 20 g of a compound ("Compound X") parenterally, by injection, and that it is desired to administer an injection volume of not more than 2 ml to minimize the pain of the injection. In this way, for a salt of Compound X to be "useful", it would need to have a solubility, in the selected aqueous cyclodext, equivalent to or greater than 10 mg / ml of Compound X in its active form. Within a series of salts, the more soluble salt 'may not be the most useful candidate for a given application. Factors such as chemical stability, hygroscopicity and precipitation potential should also be considered when selecting a candidate that has a solubility that the object solubility, but lower than the maximum determined in the sene.

On the other hand, sometimes you could in fact wish to just find the salt. with the highest solubility of all salts of a series of salts of a particular compound. In this case the "desired target solubility" is simply the highest solubility found in the series of salts by comparison of the solubilities in the balance of the various candidate salts. If for example it is desired to prepare a dry oral dosage form such as a capsule or tablet employed an inclusion complex of a salt of Compound X, then it could only be desired to find the most soluble salt available in order to minimize the amount of inclusion complex in the dosage form and therefore minimize the size of the dosage form itself. "Maximum total dose" is the maximum intended dose size, including excipients and liquids (eg, for injectable) that are to be included in the dosage form, considering the patient or patient population to which allocate the dosage form. Typically it is considered that a maximum total dose is for an injectable of about 2 ml for adults. A maximum total dose for a tablet or capsule is typically a pair of beads to ensure that the dosage form is swallowable. The sizes, weights and volumes are "intended" meaning that they can be changed or altered depending on the specific population of patients. This invention is based, inter alia, on the discovery that for a particular cyclodextrin, the solubility of a particular compound in an aqueous solution of a cyclodextrin is not independent of the salt employed. That is, different salts of the same compound can often present solubilities in the same cyclodextri to differ widely. The phenomenon of differential solubility presented by different salts of a compound in the same cyclodextrin was not known in the art until now. It has also been determined that the position within the order of solubility, ie the increasing or decreasing order of solubility of a series of salts in an aqueous cyclodextrin solution is not necessarily related to the order of the solubility of the salt in water. The discovery of such differential solubility of different salts in a particular cyclodextrin is surprising and unexpected according to conventional wisdom which says that the total solubility of a compound that can be extracted in a solution containing a cyclodextrin is the sum total of the solubility of all the species of the compound that exists in various forms in the solution. In a solution containing cyclodextrin this could be represented by the following expression: Total Drug Solubility = Fraction of free drug in the un-ionized form + Fraction of complex drug in the un-ionized form + Fraction of drug loaded in free form + Fraction of drug loaded in complex form.

Furthermore, it is generally thought that a salt form of an iotable compound is dissolved in an aqueous solution and completely dissociates according to its solubility product as described by the expression.

(DH X) < > DH- + X-where Ka DH < > D + H * DHX is the acid addition salt of a basic compound, DH * is the charged form in solution, X ~ is the contraction D is the un ionized form in solution, H is the proton concentration dictated by the pH of the dissolution, and Km is the dissociation constant.

Therefore, it is expected that for a particular compound various salt forms have different aqueous solubilities dictated by KPB. The above expressions further indicate that in a constant ionization state (ie, at constant pH), the difference in solubility between various salt forms of a particular compound should be the same in the presence and absence of a particular cyclodextrin. Thus, if a phase diagram of solubility of a specific compound in an aqueous solution containing a specific cyclodextrin or function of the concentration of cyclodextrin is constructed, the different salts of the compound would be represented as straight lines with different ordinates at the origin, but with the same slope. Thus, based on the conventional belief there is no reason to expect that different salts of a particular compound will be differentially solubilized in the same cyclodextrin since it is thought that the counterion plays no role in the complex formation process. Furthermore, the phenomenon of differential solubility is important because it makes possible the ability to increase the charge of a particular compound in a cyclodextrin by analyzing a series of different salts of that compound and selecting a salt that gives a desired high solubility, thereby allowing the use of a lower amount of cyclodextrin with respect to a less soluble salt in the cyclodextrin. The phenomenon is especially important in the case of parenteral administration (ie, by injection) because, assuming a constant concentration of inclusion complex in water, the injection volume can be reduced by selecting a salt very soluble in appropriate cyclodextrin. As indicated above, when salts very soluble in cyclodextrin are located, the invention also provides an opportunity to reduce the size of dry dosage forms (such as tablets and capsules by using smaller equivalent amounts of inclusion complex with respect to amounts of inclusion complex of soluble salts in ciclodextpna.

BRIEF DESCRIPTION OF LQS FISURQS Figure 1 is a phase diagram of solubility which is a representation of the maximum solubility in equilibrium of a seen of salts of the ziprasidone compound as a function of the concentration of SBECD in water. The ordinate (Y axis) is the Drug Solubility (the units are millimolar) and the abscissa (e X) is the concentration of BECD (also in illirnolar units). The methodology used is explained in the following table: Detailed Discussion The amount of medicinal compounds to be administered to a patient is an effective amount. The quantity, the administration mode such as oral, parenteral, etc. and the L4 regime Dosage (for example, without the dose to be divided1 and its frequency of administration) will of course vary with the compound or administer, the patient population, and so on. The amount of cyclodextrin used in a particular formulation will be an amount that increases bioavailability. Small amounts of cyclodextrin, even when present in a dosage form that is a mixture, can improve bioavailability by forming an inclusion complex m, thereby increasing the biodiepitability of the drug relative to the drug without forming the complex. In general, the amount of cyclodextrin in a formulation is usually such that the molar ratio of cyclodextrin to drug is between 0.1: 1 and 100: 1, preferably between 0.25: 1 and 10: 1, more preferably between 0.5: 1 and 5: 1. If the formulation is an aqueous solution, it may contain cyclodextrin within a wide range of concentration, for example from 5% w / v to more than 100% w / v. At high concentrations of cyclodextrins, the formulations become somewhat viscous and are suitable for oral administration as elixirs or syrups. The invention is applicable to cyclodextrins in general, including those that are known at present. Suitable cyclodextrins include α, β and β-cyclodextrins, methylated cyclodextrins, hydroxypropyl-β-cyclodextrin (HPBCD), hydroxyethylated β-cyclodextrin (HEBCD), branched cyclodextrins in which one or two glucose or maltose enzymatically binds to the cyclodextrin ring , ethyl- and ethyl-carboxymethylcyclodextrins, dihydroxypropyl-cyclodextrins and sulfoalkyl ether cyclodextrins. The degree of substitution is not considered critical and the aforementioned cyclodextrin can have virtually any degree of substitution (per complete cyclodextrin molecule) known in the art. Lae mixtures of cyclodextrin, as well as individual species, are suitable in the preparation of dosage forms according to the invention. HPBCD is well known in the art, see for example Publication R 81 215 entitled "Encapsm HPB" from Oanssen Biotech NV SBECD is also known and has been described in US Patents 5,375,545 and 5,134,127. both of Stella et al., which are incorporated herein by reference in their entirety. The pharmaceutically acceptable basic or acid addition salts of a compound capable of forming salts can be prepared as is known in the art by conventional methodology treating a solution or suspension of the compound with about one chemical equivalent of a pharmaceutically acceptable acid or base. , as appropriate, depending of course on whether the compound forms acid addition salts or basic addition salts. The salt can be isolated by conventional methods, such as by filtration when the salt precipitates spontaneously (for example, as a crystalline material), or can be isolated otherwise by concentration and / or addition of non-solvent. For example, the salts employed in the following Examples were made by first weighing a quantity of ziprasidone free base and adding it to a solvent, typically an organic solvent, water or a mixture of two or more solvents. The solvent or solvents employed may depend on whether it is desired to isolate the salt from a suspension or a solution. If you want to isolate the salt from a solution, the solvent can be heated, with stirring, to facilitate dissolution. About one molar equivalent of an acid or a base, as appropriate, or a slight excess, corresponding to the counterion, is added with agitation. After a period of time that can be determined by simple experimentation, typically hours, the solids can be collected by filtration and washed. An inclusion complex of a pharmaceutically acceptable salt of a compound can be prepared by standard methodology. That is, an inclusion complex of a desired pharmaceutically acceptable salt can be prepared in situ by adding the salt directly to a solution prepared in advance of cyclodextrin in water (or other suitable pharmaceutically acceptable aqueous medium) in an amount sufficient to prepare a solution of the product of the desired concentration. Alternatively, the drug and the cyclodextrin may be added to the water separately or together as a mixture. The product solution can be used immediately or stored (at room temperature or at low temperature) depending on the expiration period of the inclusion complex. A pharmaceutically acceptable preservative or other excipients could be added to make the dosage form stable against chemical, physical or microbial degradation. If SBECD is used as cyclodextrin, as SBECD is generally used in the form of its sodium salt, the product solution can be used as such (with reheating at room temperature if the solution was stored) to be administered to patients, without being Necessary isotonicity adjustment. If it is necessary to adjust the isotonicity, it can be adjusted in the manner known in the art by adding an appropriate amount of an isotonicity adjusting agent. Alternatively, the inclusion complex of a salt in aqueous cyclodextrin can be isolated first, usually by lyophilization. The Isolated Inclusion Complex can be stored at room temperature during its expiration period (usually at least two years) and reconstituted in a product solution when needed. When a product solution is needed, can it be done by dissolving the isolated inclusion complex in water? another aqueous medium in an amount sufficient to generate a solution of the concentration required for oral, parenteral or other administration to patients. If it is necessary to adjust the isotonicity, it can be achieved in conventional manner as is known in the art by adding an isotonicity adjusting agent. Alternatively, a solid physical mixture can be prepared that includes a salt of a drug and a cyclodextrin in the form of a tablet or capsule that dissolves in the gastrointestinal fluids after oral ingestion. Such mixtures could also be incorporated in buccal, sublingual, nasal, topical or transdermal dosage forms. Such compositions could also be incorporated as solutions or suspensions in soft gelatin capsules. The phenomenon of the different solubilities for different salts in a given cyclodextrin is general. The invention is not limited to any particular compound or class of compounds or to any particular cyclodextrin. The invention is more particularly applicable to salts of general form. In addition, the invention is not limited to any dosage form or specific route of administration. Rather, the invention is useful whenever an increase in the solubility of a salt of a compound is desired. For purposes of illustration, the following exposure is directed to a particular compound, ziprasidone, which has the structure It is described in US Pat. No. 4,832,031, has utility as a neuroleptic and is therefore useful as an antipsychotic. Naturally, initiates in the art will realize that the teachings concerning the ziprasidone salts are also generally applicable to other salts. A solubility test of various ziprasidone salts on cyclodextrin 8SBECD and HPBCD was performed comparing the solubility in the maximum equilibrium of each salt in an equal amount of cyclodextrin. You can imagine and use many different experimental protocols. The following protocol uses 40% aqueous cyclodextrin as a standard solution for comparison of the solubilities in the salt balance, although this concentration should not be considered as limited. Other concentrations may also be used to serve as a comparison standard. The HPBCD used was purchased from Uacker Chemie. The SBECD employed had a degree of substitution with sulfobutyl groups of 6.5, average, per molecule of β-cyclodextrin, prepared by a procedure according to the indications described in Example 3 of the present US Pat. No. 5,376,645. A solution of cyclodextrin (SBECD or hpbcd) AL 40% (w / v) in water was prepared by adding 200 g of cyclodextrin to a 500 ml beaker containing approximately 250 ml of deionized water and a magnetic stirring bar . The contents were stirred until sufficient time had usually ended for about an hour. The solution was then transferred to a 500-milliliter graduated flask and filled with deionized water. Five mJ of the volumetric solution were pipetted into a 10-milliliter glass vial with a screw cap. An excess of the test candidate solid ziprasidone salt and a magnetic stir bar were added to the vial. The contents of the vial were stirred for 4 days at room temperature to give sufficient time for equilibrium to be reached. After extraction of the magnetic agonist, the sample had an undissolved solid present, which indicated a saturated solution under the conditions used. The content was filtered through a 0.2 μm Millex filter into a clean vial with screw closure and the concentration of the drug was determined by an HPLC method. As an example of HPLC analysis, the amount of dissolved compound can be determined using a C18 Puresil column (Trade Mark of Waters Associates) with an isocratic mobile phase composed of 60% 0.05 M onopotassium phosphate buffer and 40% methanol, at a flow of 2 ml / mm. at 40 ° C. The detection can be by UV absorption at a wavelength of 229 n. Quantification can be easily carried out by comparing the height (or area) of the HPLC peak with the height (or area) of the peak taking from a standard representation of the concentration versus the height (or area) of reference standards of known concentration. As usual, the reference standard concentrations of zipraeidone are selected such that they comprise a linear range of concentration versus absorbance with the UV detector employed. It may be necessary to make serial dilutions of the saturated solution in the equilibrium obtained after filtering the solution from the analysis vial to be within the linear range of the reference standard line, and the dilution could be carried out by addition of isocratic mobile phase . The above procedure was also used to determine the solubility of ziprasidone in other concentrations of cyclodextrin. By doing this and using the data to construct solubility phase diagrams of different ziprasidone salts, it was determined that the solubility phase diagrams were linear for each salt, but that the slopes were different, thus demonstrating that different ziprasidone salts were obtained. they may have different solubilities at equilibrium in the same cyclodextrin. Figure 1 shows the phase diagram of solubility generated by doing this for different ziprasidone salts. Using the previous HPLC procedure (including? column and isocratic mobile phase) different ziprasidone saltse were analyzed to determine the equilibrium solubility of each in 40% HPBCD and 40% SBECD. The results are given in Table 1. Table I: Solubility of ziprasidone salts in water and cyclodextrin solutions at 40% Note: mgA indicates the weight (in mg) of ziprasidone calculated as the free base, Molecular weight: 412.9; NE = No. tested.

Molecular weight of ß-c? Clodextpna-sulfobut? -ether (SBECD): 2163; 40% (w / v) = 400 g / l ~ 0.18 M; Molecular weight of hydroxypropyl-β-cyclodextr p na (HPBCD): 1309; 40% (w / v) = 400 g / l = 0.31 M. As mentioned above, the order of solubility of a series of salts in water does not necessarily go in parallel with the order of solubility in solution of aqueous cyclodextrin. Table 1 illustrates this issue. For example, ziprasidone eslate salt is twice as soluble in water as tartrate. The solubilities of these two salts are more or less the same in aqueous HPBCD and inverted in aqueous SBECD. Table 1 indicates that for the particular ziprasidone candidate salts and the cyclodextrin solutions tested, the highest solubility of ziprasidone can be achieved by dissolving ziprasidone esylate in 40% SBECD. To administer a therapeutic dose of ziprasidone 80% mg / day of ziprasidone to a patient, the volume of solution at 40% needed can be calculated as follows: 80rngA / day x 1 rnl / 44 mgA 0 1.8 ml / day In this manner with the present invention, as in the above example of ziprasidone salts *, therapeutically useful salt inclusion complexes, ie, inclusion complexes administering? Na? desired therapeutic dose. As seen in Figure 1, the solubility of the ziprasidone salt is linear as a function of the concentration of cyclodextrin in water. This illustrates that the maximum amount of a particular salt that can be dissolved in an aqueous cyclodextrin can be measured in the manner known in the art directly from such a solubility phase diagram (i.e., by using the appropriate line as a graph). of calibration), or calculated if the slope (and the ordinate at the origin, is not zero) of the appropriate line has been obtained. As mentioned previously, the mcluding complex can be formulated for oral or parenteral administration, usually intramuscular administration, to a patient. Subcutaneous and intravenous administration is also feasible. Inclusion complexes can also be administered orally in conventional forms, for example, as tablets, capsules, powders for oral suspensions, and unit dose containers containing a single dose (referred to in the art as "sachets"). They can also be administered as buccal or sublingual tablets, with nasal sprays, in topical creams, in transdermal patches and as suppositories. The following examples further describe and illustrate the invention: Loe Examples 1 and 2 illustrate the invention with ziprasidone.

EXAMPLE 1 A SBECD solution of 300 mg / ml was prepared by dissolving SBECD in a pharmaceutically acceptable aqueous medium such as water. Ziprasidone rinsylate was dissolved in the SBECD solution to give a concentration of 27.3 g / ml (20 mgA / ml). The solution was sterile filtered through a 0.2 μr filter. Glass vials were filled with the filtered solution to prepare a solution of the product that can be administered orally or intramuscularly, intravenously or subcutaneously.

EXAMPLE 2 A product solution is prepared as described in Example 1. The glass vials containing the product solution were loaded in a lyophilizer and the product solution was lyophilized. The vials and their lyophilized contents were stored at room temperature until needed, at which time they were reconstituted with water or a pharmaceutically acceptable aqueous buffer for oral administration or intramuscularly, intravenously or subcutaneously. The following examples illustrate how to calculate the dosage levels of particular inclusion complexes to administer a particular dose and also how to minimize the injection volume.

EXAMPLE 3 Compound A, a drug poorly soluble (in water), is a carboxylic acid having a molecular weight of 350. It is administered at a preferred dose of 75 mgA / day in adults ("mgA" refers to milligrams of compound active, free acid) and 25 mgA / day in children. The following series of basic addition salts have the solubilities indicated in 40% (w / v) aqueous cyclodextrin: free acid 2 mgA / ml Salt A 13 mgA / rnl Salt B 38 ngA / rnl Salt C 52 mgA / ml Salt D 37 rngA / rnl Salt E 5 mgA / ml For its administration as an injectable, a target volume of no more than 2 ml was set for adults and not more than 0.5 ml. for children. It is determined that Salt B (2.0 ml of injection to administer 75 mgA) and Salt C (1.4 ml of injection volume to administer 75 mgA) are suitable for adults. It is determined that only salt C is suitable for children (0.48 thousand to administer 25 rngA) since all other salts need more than 0.5 ml to administer 25 rng.

E3E1PLQ * ziprasidone rilelate 1 g of ziprasidone free base was added to 20 rnl of isopropyl alcohol followed by 140 mg of methanesulfonic acid. After a few minutes the suspension that formed was thickened and the color clarified somewhat when precipitated. The salt was collected by filtration through a 5 μ membrane of polytetrafluoroethylene.

EXAMPLE 5 Ziprasidone esylate 1 g of ziprasidone free base was added to 45 rnl of THF and 1 ml of water and the mixture was heated to 60 ° C while stirring. The mixture was maintained at 60 ° C for two hours, at which time all the free base had dissolved. 155 mg was added. Ethanesulfonic acid and stirring was maintained at 60 ° C for 2 more hours. During this time the mixture changed from light orange to cloudy, at which point heating was stopped and the salt started to precipitate. The mixture was allowed to cool to room temperature overnight while stirring was maintained. The salt was then collected by filtration as in Example 5 EXAMPLE 6 Ziprasidone Tartrate 1 g of ziprasidone free base of 60 ml of water was added and the resulting suspension was heated for 3 hours at 50 ° C with stirring. 900 rng of L-tartaric acid was added. The heating was maintained at 50 ° C and the stirring for a further 6 hours and then the mixture was stirred at 40 ° C overnight. The solution was then allowed to cool and the salt was collected as in Example 5.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for locating one or more salts of a compound, said salts having a solubility in a cyclodextrin equal to or greater than a desired target solubility, which includes obtaining a series of salts of said compound, determining the solubility in the equilibrium of each salt of said series in an aqueous solution of the aforementioned cyclodextrin and comparing each measured solubility with said objective solubility.

2. A method of determining a useful salt, from a series of salts of a particular medicinal compound, for use in the preparation of a composition of matter comprising said salt and a cyclodextrin, said process consisting of: a. obtain said series of eale; b. determining the solubility in the equilibrium, in aqueous solution of cyclodextrin, of each of said salts of the mentioned series; and c. selecting, as the above-mentioned useful salt, a salt of said series having a solubility in said cyclodextrin solution equal to or greater than the desired objective solubility.

3. A method of determining a useful salt, from a series of salts of a particular medicinal compound, for use in the preparation of a composition of matter comprising an inclusion complex of said salt in a cyclodextrin, consisting of said procedure in: a. determine a quantity of said medicinal compound required for therapeutic efficacy, b. selecting a maximum total dose to which said amount of medicinal compound is administered; c. calculating the minimum required solubility of a salt of said compound necessary to formulate the maximum total dose quoted; d. obtain the series of salts cited: e. determining the solubility in the equilibrium of each of said salts in said cyclodextrin; and f. selecting, as the above-mentioned useful salt, a salt of the aforementioned series having an equilibrium solubility in said cyclodextrin sufficient to allow preparing a total dose equal to or less than the maximum total dose cited.

4. A composition of matter comprising a salt of a compound and a cyclodextrin, said salt having been located or selected using a process as defined in claim 1.

5. A composition of matter comprising a salt of a compound and a cyclodextrin, said salt having been located or selected using a method as defined in claim 2.

6. A composition of matter comprising a salt of a compound and a cyclodextrin, said salt having been located or selected using a process such as is defined in claim 3.

7. - A composition as defined in claim 4, which is a physical mixture of said salt and said cyclodextrin.

8. A composition as co-defined in claim 5, which is a physical mixture of said salt and said cyclodextrin.

9. A composition as defined in claim 6, which is a physical mixture of said salt and said cyclodextrin.

10. A composition as defined in claim 4, which is a preformed dry inclusion complex of said complex salt with said cyclodextrin.

11. A composition as defined in claim 5, which is a preformed dry inclusion complex of said salt complexed with said cyclodextrin.

12. A composition as defined in claim 6, which is a preformed dry inclusion complex of said salt complexed with said cyclodextrin.

13. A composition as defined in claim 4, which is an aqueous solution.

14. A composition as defined in claim 5 ,. which is an aqueous solution.

15. A composition as defined in claim 6, which is an aqueous solution. RF SUMMARY OF THE INVENTION A method for locating one or more salts of a compound, said salts having a solubility of a cyclodextrin equal to or greater than an objective solubility of a cyclodextrin equal to or greater than a desired target solubility, including obtaining a series of salts thereof. compound, measure the solubility in the balance of each salt of said series in the cyclodextrin mentioned and compare each measured solubility with said objective solubility. P97-360 PF / fac