KITS COMPRISING CONTAINERS WITH AT LEAST ONE SOLID CATALYTICALLY ACTIVE COMPOUND, AND THEIR USES IN SOLID STATE REACTION

Abstract

Subject matter of the present invention are kits comprising containers with at least one solid catalytically active compound, their uses in processes for simulating and predicting the transformation of a compound that is preferably a solid active pharmaceutical ingredient (API), preferably an API in combination with an excipient, in a shortened time span, into the respective degradation product(s).

Claims

1. Kit comprising the following components: Container comprising a catalyst that is 3-15% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel 60 (70-230 mesh), preferably 3-10% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel, more preferably about 5% (w/w) sulfuric acid or chlorosulfonic acid on silica gel, and/or Container comprising a catalyst that is 3-15% (w/w) KOH or NaOH absorbed on silica gel or alox, preferably 3-10% (w/w) KOH or NaOH absorbed on silica gel or alox, more preferably about 5% (w/w) KOH or NaOH on silica gel or alox, and Container comprising a catalyst that is 3-15% (w/w) KMnO.sub.4 absorbed on silica gel or alox, preferably 3-10% (w/w) KMnO.sub.4 absorbed on silica gel or alox, more preferably about 5% (w/w) KMnO.sub.4 on silica gel or alox, and Optionally a container comprising a neutral catalyst that is pure silica gel 60 (70-230 mesh) or that is pure alox.

2. Kit according to claim 1 comprising the following components: Container comprising a catalyst that is 3-15% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel 60 (70-230 mesh), preferably 3-10% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel, more preferably about 5% (w/w) sulfuric acid or chlorosulfonic acid on silica gel, and Container comprising a catalyst that is 3-15% (w/w) KOH or NaOH absorbed on silica gel or alox, preferably 3-10% (w/w) KOH or NaOH absorbed on silica gel or alox, more preferably about 5% (w/w) KOH or NaOH on silica gel or alox, and Container comprising a catalyst that is 3-15% (w/w) KMnO.sub.4 absorbed on silica gel or alox, preferably 3-10% (w/w) KMnO.sub.4 absorbed on silica gel or alox, more preferably about 5% (w/w) KMnO.sub.4 on silica gel or alox, and Container comprising a neutral catalyst that is pure silica gel 60 (70-230 mesh) or that is pure alox.

3. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) KMnO.sub.4 absorbed on alox, preferably 3-10% (w/w) KMnO.sub.4 absorbed on alox, more preferably about 5% (w/w) KMnO.sub.4 on alox.

4. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) KMnO.sub.4 absorbed on silica gel, preferably 3-10% (w/w) KMnO.sub.4 absorbed on silica gel, more preferably about 5% (w/w) KMnO.sub.4 on silica gel.

5. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) NaOH absorbed on silica gel, preferably 3-10% (w/w) NaOH absorbed on silica gel, more preferably about 5% (w/w) NaOH on silica gel.

6. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) NaOH absorbed on alox, preferably 3-10% (w/w) NaOH absorbed on alox, more preferably about 5% (w/w) NaOH on alox

7. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) KOH absorbed on silica gel, preferably 3-10% (w/w) KOH absorbed on silica gel, more preferably about 5% (w/w) KOH on silica gel.

8. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) KOH absorbed on alox, preferably 3-10% (w/w) KOH absorbed on alox, more preferably about 5% (w/w) KOH on alox.

9. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) sulfuric acid absorbed on silica gel 60 (70-230 mesh), preferably 3-10% (w/w) sulfuric acid absorbed on silica gel, more preferably about 5% (w/w) sulfuric acid on silica gel.

10. Kit according to claim 1 comprising the following component: Container comprising a catalyst that is 3-15% (w/w) chlorosulfonic acid absorbed on silica gel 60 (70-230 mesh), preferably 3-10% (w/w) chlorosulfonic acid absorbed on silica gel, more preferably about 5% (w/w) chlorosulfonic acid on silica gel.

11. Kit according to claim 1 additionally comprising the following components: Container comprising a catalyst that is 3-15% (w/w) K.sub.2Cr.sub.2O.sub.7 absorbed on silica gel, preferably 3-10% (w/w) K.sub.2Cr.sub.2O.sub.7 absorbed on silica gel, more preferably about 5% (w/w) K.sub.2Cr.sub.2O.sub.7 on silica gel

12. Kit according to claim 1 additionally comprising the following components: Container comprising a catalyst that is 3-15% (w/w) KMnO.sub.4 absorbed on silica gel or alox, preferably 3-10% (w/w) KMnO.sub.4 absorbed on silica gel or alox, more preferably about 5% (w/w) KMnO.sub.4 on silica gel or alox, and Container comprising a catalyst that is 3-15% (w/w) K.sub.2Cr.sub.2O.sub.7 absorbed on silica gel, preferably 3-10% (w/w) K.sub.2Cr.sub.2O.sub.7 absorbed on silica gel, more preferably about 5% (w/w) K.sub.2Cr.sub.2O.sub.7 on silica gel

13. Kit according to claim 1 additionally comprising the following components: container comprising a neutral catalyst that is pure silica gel 60 (70-230 mesh) or that is pure alox

14. Kit according to claim 1 in a mechanochemical process for simulating and predicting the resulting degradation products of a compound that is preferably a solid active pharmaceutical ingredient (API), preferably an API with an API or an excipient with an excipient, more preferably an API in combination with an excipient.

15. A mechanochemical process for simulating and predicting the transformation of a compound that is preferably a solid active pharmaceutical ingredient (API), preferably an API in combination with an excipient, in a shortened time span, into the respective degradation product comprising the following steps: Providing a kit according to claim 1, Exposing said compound that is preferably a solid active pharmaceutical ingredient (API), preferably an API in combination with an excipient, to said mechanochemical process, preferably a ball mill process, wherein the stoichiometric ratio of API:catalyst (weight stoichiometry) is 1:1 to 20, preferably about 1:10, and Analyzing the degradation products.

16. A mechanochemical process according to claim 15, wherein the reaction time of said process is between 10-90 minutes.

17. A mechanochemical process according to claim 15, wherein the frequency of said ball mill is between 5 to 30 Hz, preferably between 15 to 25 Hz.

18. A mechanochemical process according to claim 15, wherein the mechanochemical process is conducted at room temperature.

19. The kit according to claim 1, wherein said kit contains: Container comprising a catalyst that is 3-10% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel 60 (70-230 mesh), and/or Container comprising a catalyst that is 3-10% (w/w) KOH or NaOH absorbed on silica gel or alox, and Container comprising a catalyst that is 3-10% (w/w) KMnO.sub.4 absorbed on silica gel or alox, and Optionally a container comprising a neutral catalyst that is pure silica gel 60 (70-230 mesh) or that is pure alox.

20. The kit according to claim 1, wherein said kit contains: Container comprising a catalyst that is about 5% (w/w) sulfuric acid or chlorosulfonic acid absorbed on silica gel 60 (70-230 mesh), and/or Container comprising a catalyst that is about 5% (w/w) KOH or NaOH absorbed on silica gel or alox, and Container comprising a catalyst that is about 5% (w/w) KMnO.sub.4 absorbed on silica gel or alox, and Optionally a container comprising a neutral catalyst that is pure silica gel 60 (70-230 mesh) or that is pure alox.

Description

FIGURE DESCRIPTION

Figures

[0315] The following is a brief description of the Figures:

[0316] FIG. 1:

[0317] FIG. 1 is a chromatogram from J. Pharm. Biomed. Analysis 52 (2010) 332-344, “Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate under solid state stress conditions”. The chromatogram is showing the separation of degradation products formed in different solid forms under solid state stress conditions [DP-degradation product, A-acidic conditions, Al-alkaline conditions, N-neutral conditions (without stressor), P1-polymorph I, P2-polymorph II, and Am-amorphous form].

[0318] FIG. 2:

[0319] FIG. 2 shows a HPLC-chromatogram of clopidogrel bisulphate after milling reaction with an acidic solid phase catalyst. FIG. 2 clearly shows, that the acidic degradation product (RT 15 min), that was detected in the literature after incubation of the API with an acidic stressor at 40° C./75% relative humidity for 3 months, could also be detected in the solid phase set-up after 60 minutes process time already. The identity of the degradation product was confirmed by corresponding retention time and mass spectrum.

[0320] FIG. 3:

[0321] FIG. 3 is a comparison of acidic degradation (RT 15 min) under conventional and toolbox conditions, respectively, based on AUCs in the HPLC method.

[0322] FIG. 4:

[0323] FIG. 4 shows a degradation of clopidogrel with oxidative solid phase catalyst (KMnO.sub.4 on aluminium oxide, dry) with process times between 60 and 300 minutes. It clearly shows that there are two oxidative solid phase degradation products, but due to lack of literature data their structure and molecular weight could not be compared and confirmed. The product at retention time 12 min showed a molecular mass decreased by two mass units compared to the parent clopidogrel indicating a didehydro clodipogrel, which was reasonable and documented as an oxidized species under forced degradation conditions. However, no follow-up or second line degradation products occurred and the reaction showed a clear time-dependency following characteristic reaction kinetics.

[0324] FIG. 5:

[0325] FIG. 5 shows a DSC profile of clopidogrel bisulphate polymorph II

[0326] FIG. 6:

[0327] FIG. 6 shows DSC profile of clopidogrel bisulphate polymorph II after milling 25 Hz, 90 min. It shows, that an increased energy input with 25 Hz for 90 minutes lead to a change of the polymorphic form II to the amorphous state.

[0328] FIG. 7:

[0329] FIG. 7 shows a DSC profile of clopidogrel bisulphate polymorph II after milling 10 Hz, 90 min. It shows, that an energy input with 10 Hz for 90 minutes exhibited minor changes and higher stability compared to FIG. 6.

[0330] FIG. 8:

[0331] FIG. 8 shows the linearity data for clopidogrel bisulphate. It shows that the method had sufficient specificity to separate the API and its major degradation products at an area percent of >1% with a resolution factor of >1.5 for each peak.

[0332] FIG. 9:

[0333] FIG. 9 shows a sample of clopidogrel bisulphate with alkaline stressor Na.sub.2CO.sub.3 stored at 40° C./94% RH for 15 days.

[0334] FIG. 10:

[0335] FIG. 10 shows an overlay of three injections of the oxidative sample after milling for 60 minutes at 25 Hz proving that the method delivered reliable and reproducible results.

[0336] FIG. 11:

[0337] FIG. 11 shows an overlay of acidic solid phase samples of three independent milling experiments after 30 min at 25 Hz demonstrating the reproducibility of the milling experiments.

[0338] FIG. 12:

[0339] FIG. 12 shows an overlay of oxidative solid phase samples of three independent milling experiments after 30 min at 10 Hz demonstrating the reproducibility of the milling experiments.

[0340] The invention was further illustrated by Examples.

EXAMPLES

Example 1: Proof of Concept

[0341] The first experiment was focused on a simple, well characterized API and other molecules with low structural complexity but with representative functional groups. They were systematically combined with a selection of potentially suitable catalysts. The solid phase reactions were initiated by ball milling for energy transfer in a controlled environment. In a first experimental set-up the oxidation in solid phase systems was analysed including a systematic evaluation of various catalysts, carrier matrices and reaction conditions.

[0342] The following analytical methods were implemented. Two solid phase oxidation reactions were prepared. The catalyst used was KMnO.sub.4 on silica and the active reaction container was a ball mill. The result achieved was oxidation of 4-methoxybenzyl alcohol to yield p-anisaldehyd and diphenylsulfide to yield diphenylsulfoxide and diphenylsulfone, respectively. Based on the chemical structure, both oxidation products could be expected and were documented in literature as oxidative impurities, showing that the concept of the invention of initiating a degradation in a mechanochemical process did indeed work with an enormous reduction of the necessary time for doing so compared to the conventional method.

[0343] The degradation process is shown in the below structures:

##STR00001##

[0344] In another successful experimental set-up it could be demonstrated that differences in oxidation environment and oxidative power through varying catalysts could influence the reaction pathway and product, respectively. Thus, reaction of diphenylsulfide on aluminium oxide yielded solely the higher oxidation state product diphenyl sulfone, but no diphenylsulfoxide.

##STR00002##

[0345] Additionally, it was possible to control the yield of oxidation products depending on the quality of the catalyst, thus higher yields could be obtained with traces of moisture (or solvent) within the catalyst indicating higher degradation rates of solid formulations caused by increased water content, storage in a high humidity environment or selection of inadequate primary packaging material.

Example 2: Selection of Catalytic Systems

[0346] The following catalysts were selected for future standard set-up of the solid phase reaction platform:

[0347] KMnO.sub.4 on silica (dry)

[0348] KMnO.sub.4 on silica (39% H.sub.2O)

[0349] KMnO.sub.4 on aluminium oxide (dry)

[0350] Silica sulfuric acid

Example 3: Final Experimental Set-Up of a Solid Phase Prediction Platform

[0351] A study with clopidogrel was initiated. For clopidogrel detailed data on degradation under thermolytic, acidic and alkaline conditions were available and hence, a benchmark comparison of both methods (literature vs. solid phase reaction platform) was executed. The below data were obtained from J. Pharm. Biomed. Analysis 52 (2010) 332-344, “Characterization of degradation products of amorphous and polymorphic forms of clopidogrel bisulphate under solid state stress conditions”:

TABLE-US-00001 Generation of solid state stress samples. Replicate sample numbers Light chamber study HPLC analysis Dark chamber study 1.2 × 10.sup.6 lx h HPLC analysis LC-MS fluorescent light and pH effect Additive pH.sup.a 1 month 3 months 3 months 200 Wh/m.sup.2 UV light LC-MS Without addtive — 2.7 3 3 1 3 1 Acidic Oxalic acid 1.3 3 3 1 3 1 Alkali Sodium carbonate 10.1 3 3 1 3 1 .sup.apH of the microenvironment was determined by the method given by Serajuddin et al. [18].

[0352] FIG. 1 stems from the same source and shows a chromatogram showing separation of degradation products formed in different solid forms under solid state stress conditions [DP-degradation product, A-acidic conditions, Al-alkaline conditions, N-neutral conditions (without stressor), P1-polymorph I, P2-polymorph II, and Am-amorphous form]. The part marked with “*” shows that only amorphous form leads to formation of DP-3 under neutral conditions.

[0353] To compare the results clopidogrel bisulfate was mixed with oxidative, acidic and alkaline solid phase catalysts, processed in a ball mill under standard conditions and the products were analysed by WAXS, DSC or HPLC-MS, respectively. For HPLC-MS, the analytical system from literature was transferred and implemented in the lab, accordingly, the solid phase reaction of clopidogrel bisulfate under various conditions could be compared to literature data as shown in the FIG. 2 etc.

[0354] FIG. 2 shows a HPLC-chromatogram of clopidogrel bisulphate after milling reaction with an acidic solid phase catalyst. FIG. 2 clearly shows, that the acidic degradation product (RT 15 min), that was detected in the literature after incubation of the API with an acidic stressor at 40° C./75% relative humidity for 3 months, could also be detected in the solid phase set-up after 60 minutes process time already. The identity of the degradation product was confirmed by corresponding retention time and mass spectrum.

[0355] Additionally, the quantity of degradation was compared between the conventional forced degradation conditions and the solid phase conditions showing a comparable amount after 60 minutes process time already. This is shown FIG. 3.

[0356] FIG. 3 is a comparison of acidic degradation (at RT for 15 min) under conventional and solid state catalytic conditions, respectively, based on AUCs in the HPLC method.

[0357] Another experiment was set-up with clopidogrel and an oxidative solid phase catalyst (KMnO.sub.4 on aluminium oxide, dry) to demonstrate oxidative degradation and time-dependency of degradation mechanism. The result is shown in FIG. 4.

[0358] FIG. 4 shows a degradation of clopidogrel with oxidative solid phase catalyst (KMnO.sub.4 on aluminium oxide, dry) with process times between 60 and 300 minutes.

[0359] FIG. 4 clearly shows that there are two oxidative solid phase degradation products, but due to lack of literature data their structure and molecular weight could not be compared and confirmed. The product at retention time 12 min. showed a molecular mass decreased by two mass units compared to the parent clopidogrel indicating a didehydro clodipogrel, which was reasonable and documented as an oxidized species under forced degradation conditions.

[0360] Undoubtedly, a clear and expected time-dependency of the reaction could be proven, since the product peaks increased with time, and no additional side-products or follow-up products were formed supporting the reliability of the method and data generated.

[0361] As documented in literature clopidogrel bisulphate exists in one amorphous and two polymorphic forms, polymorph II was used for the experiments described. To elucidate the stability and detect changes of the polymorphic form after energy input a simple experimental set-up with the API and no further additives was executed and the polymorphic form was analysed by WAXS (wide-angel X-ray scattering) and DSC (differential scanning calorimetry).

[0362] The following FIGS. 5-7 demonstrate the applicability of the solid phase reaction platform to predict stability and changes of polymorphs based on DSC chromatograms.

[0363] FIG. 5 shows the DSC profile of clopidogrel bisulphate polymorph II, FIG. 6 shows the DSC profile of clopidogrel bisulphate polymorph II after milling 25 Hz, 90 min and FIG. 7 shows the DSC profile of clopidogrel bisulphate polymorph II after milling 10 Hz, 90 min.

[0364] FIG. 6 clearly shows, that an increased energy input with 25 Hz for 90 minutes lead to a change of the polymorphic form II to the amorphous state, whereas FIG. 7 with 10 Hz for 90 minutes exhibited minor changes and higher stability. These experiments could be used to evaluate the stability of various polymorphic forms in general, but could also indicate the stability/instability during industrial processing and manufacturing.

Example 4: Test of the Robustness and Repeatability of Solid Phase Experiments

[0365] To evaluate the reliability and robustness of the analytical method a “mini-validation” with 3 repetitions was performed.

TABLE-US-00002 TABLE 1 Data on linearity for concentrations between 100 μg/mL and 1000 μg/mL clopidogrel bisulphate Weigh 1 [mg] Weigh 2 [mg] W theoretical 20.00 20.00 W ref. 20.29 20.19 Faktor(W theoretical/W ref) 0.99 0.99 conc Sample [μg/ml] Area Area.sub.Korr STD 100 ug/ml 100.00 437968 431708 STD 100 ug/ml 100.00 436821 430578 STD 325 ug/ml 325.00 1525713 1503906 STD 325 ug/ml 325.00 1527693 1505858 STD 550 ug/ml 550.00 2630248 2592655 STD 550 ug/ml 550.00 2635584 2597914 STD 775 ug/ml 775.00 3802703 3748352 STD 775 ug/ml 775.00 3741872 3688390 STD 1000 ug/ml 1000.00 4804286 4735620 STD 1000 ug/ml 1000.00 4783446 4715077 slope 4801 intercept −45458.6 correlation coefficient (R.sup.2) 0.9998

[0366] FIG. 8 shows the linearity data for clopidogrel bisulphate. As shown the method had sufficient specificity to separate the API and its major degradation products at an area percent of >1% with a resolution factor of >1.5 for each peak.

[0367] FIG. 9 shows a sample of clopidogrel bisulphate with alkaline stressor Na.sub.2CO.sub.3 stored at 40° C./94% RH for 15 days.

[0368] The reproducibility of the HPLC method was tested by using a sample from the solid phase experiments with mechanochemical activation which was injected three times. It could be proven as shown in FIG. 10, that the method delivered reliable and reproducible results indicating the relevant differences in the tested samples. The same can be seen in Table 2. FIG. 10 shows an overlay of three injections of the oxidative sample after milling for 60 minutes at 25 Hz.

TABLE-US-00003 TABLE 2 Reproducibility of the HPLC method (peak areas of degradation products of 3 repetitions) Sample Area Area Area Area Area Area Area Area Area API RT 11.949 RT 14.401 RT 18.808 RT 20.192 RT 29.784 API + Na.sub.2CO.sub.3 4156530 104669 66062 89199 31025 5543 API + Na.sub.2CO.sub.3 4170985 104045 70535 97294 30680 6084 API + Na.sub.2CO.sub.3 4151008 107364 71851 98468 29592 4577 Mean 4159508 105359 69483 94987 30432 5401 stdv (+/−) 10316 1764 3035 5047 748 763 RSD [%] 0.25 1.67 4.37 5.31 2.46 14.13 API RT 6.908 RT 7.213 RT 7.678 RT 12.005 RT 14.452 RT 21.968 RT 29.386 RT 29.795 N + API 3833025 71476 12439 40747 30677 51828 344834 31251 49522 N + API 3808011 71145 11681 34730 36490 56604 326999 32128 51076 N + API 3817469 71593 11234 39508 40008 46291 344190 29532 49532 Mean 3819502 71405 11785 38328 35725 51574 338674 30970 50043 stdv (+/−) 12630 232 609 3177 4712 5161 10116 1321 894 RSD [%] 0.33 0.33 5.17 8.29 13.19 10.01 2.99 4.26 1.79 API RT 14.424 O + API 4409692 79403 O + API 4398056 81197 O + API 4397183 75577 Mean 4401644 78726 stdv (+/−) 6984 2871 RSD [%] 0.16 3.65

[0369] Additionally, the reproducibility of the milling experiments was demonstrated for the acidic and the oxidative catalyst by comparing the individual chromatograms proving reliable and reproducible results as can be seen in FIGS. 11 and 12 as well as in Table 3.

[0370] FIG. 11 shows an overlay of acidic solid phase samples of three independent milling experiments after 30 min at 25 Hz.

[0371] FIG. 13 shows an overlay of oxidative solid phase samples of three independent milling experiments after 30 min at 10 Hz.

TABLE-US-00004 TABLE 3 Reproducibility test of milling method. Obtained peak areas of degradation products of 3 repetitive milling experiments Sample Area Area Area Area API RT 14.653 API + O 4337968 108886 API + O 4412617 106293 API + O 4347670 105284 4366085 106821 40589 1858 0.93 1.74 API RT 6.889 RT 11.845 RT 21.849 API + N 3758087 59155 94478 321630 API + N 3648396 63931 87095 357103 API + N 3666035 56458 65619 316246 3690839 59848 82397 331660 58902 3784 14992 22198 1.60 6.32 18.20 6.69