Summary of the Invention:

This invention is directed at a mechanochemical process using at least one solid catalytically active compound for simulating or capturing the transformation over time of a solid pharmaceutical composition in a shortened time span and the respective degradation pathways to convert at least a part of a solid compound composition into the respective transformation (degradation) products. The process is accomplished with chemically stimulating energy, in which an active reaction container like a ball mill is filled with a reaction mixture, the reaction mixture comprising said solid compound composition and -if suitable - at least one solid catalyst. Often, the solid compound composition is being brought in operative contact with at least a part of the active reaction container and in contact with the at least one solid catalyst. Most preferably the process is a substantially solvent-free process (whereby residual solvents, crystalline solvates, water content as residual water or bound as hydrates comprised in the composition are not meant by this solvent-free, thus meaning that solvent-free process is a process free from additional solvent). In addition, the invention also encompasses an analytical process in which the composition mixture remaining in the active reaction container at the end of a process is analyzed, a degradation product derived from the mechanochemical process according to the invention, as well as a medicament comprising the same. In addition, the invention further encompasses an analytical kit comprising an assortment of at least three separate catalyst-containers A-C (for example containing three different catalytic systems (e.g. acidic basic and/or oxidative catalytic systems)) for use in the mechanochemical process and/or the analytical process according to the invention and the use of the mechanochemical process according to the invention to determine various data. These data can be used for the prediction of degradation pathways, identification of real degradation and/or transformation products and not limited to the preparation of specific degradants and transformation products as impurities of the drug substance or the drug product. Background of the invention:

Looking into the transformation of solid materials over time is one key element of material science. The current invention is drawn to providing a method with which to capture or simulate the effects the immediate environment has on a solid structure in a shortened/accelerated time span. One of the cores of the invention is the simulation of such effects/changes without involving fluids like solvents (or at least only at a very marginal degree). The invention is mostly focussed on chemical solids (or mixtures thereof) including inorganic substances like salts, pure metals or alloys, as well as organic substances like polymers, protein structures, DNA-crystals, or small organic molecules as well as pharmaceutical excipients to name but a few. One of the most important classes of solid chemical substances or especially mixtures thereof on which the method of the invention can be used most effectively are pharmaceutical solid formulations. Pharmaceutical solid formulations are complex, multi component mixtures showing complex reaction and degradation pathways. Solid forms of drugs and medicinal products i.e. tablets, dragees, pills, capsules, etc. account by far for the majority of drugs prescribed by physician or sold over-the-counter in pharmacies (covering more than 80% of the pharmaceutical global market). Despite looking fairly stable and inert to chemical reactions, they are in fact multi-component and multi-phase systems, which should provide a complex but stable matrix, however, over the time instability is induced by morphological changes, interface reactions, elemental or other impurities or external factors triggered by the packaging material or environment (light, oxygen, etc.). In fact, the majority of pharmaceutical companies face massive problems to solve solid phase related issues due to lack of expertise in-house and very limited commercial availability of experts in this field for pharmaceutical application. The pharmaceutical industry does make use of the scientific expertise at research institutes and universities to answer principal questions and to obtain a better understanding of solid phase reactions, however, the focus of such purely research based approaches is often not suitable to answer questions from a drug developmental point of view. In addition, the tests used and known so far are highly time consuming causing a major delay.

In general, experimental setups for industry need to be easy, robust, feasible, scalable and flexible and also repeatable (i.e. different formulations, dosage forms, polymorphs, etc.) and must deliver reproducible results. The aim of the current invention was to identify a versatile strategy for minimizing risks is to simplify the experimental setup, standardize and reduce potential influencing factors, mimicking the reaction conditions in a solid phase system. It is also drawn to using the solid phase instead of solution phase to obtain more realistic results with a high quality impact defining shelf-life limits, storage conditions and specification limits. The inventive process should also be very fast and effective. The main characteristics of the current invention is that it allows easy to use flexible operations, simulation of various conditions in a highly predictive manner, the possibility to execute cross experiments for optimizing data output with a minimized experimental matrix, lower material usage. Most importantly the process according to the invention gives fast and reliable (and also repeatable) results for drug development processes and deviation management during routine manufacturing in the post-marketing phase, especially if compared to the known processes used as standard in industry also using much lower amounts of material than the processes as described in the relevant regulatory guidelines. It allows for a concept for efficient evaluation and simulation of solid phase reactions as service platform for the pharmaceutical industry and is applicable at various stages of the drug development process in a very flexible way and supports faster drug development with optimized outcome and lower failure rates and in addition also using much lesser amounts of material.

Description of the Invention:

In the major aspect the current invention is drawn to a mechanochemical process to convert at least a part of solid chemical substances or mixture thereof into the respective transformation products, the process being accomplished with chemically stimulating energy, in which an active reaction container is filled with a reaction mixture, the reaction mixture comprising said solid compound composition and optionally at least one solid catalyst or solid catalytically active compound. Most preferably this mechanochemical process is for simulating or capturing the transformation over time of a solid pharmaceutical composition in a shortened time span and the respective degradation pathways. Preferably, these solid chemical substance is a solid pharmaceutical composition. This major aspect of the current invention is also drawn to a mechanochemical process for simulating or capturing the transformation over time of a solid pharmaceutical composition in a shortened time span and the respective degradation pathways converting at least a part of solid chemical substances or mixture thereof into the respective degradation (or transformation) products, the process being accomplished with chemically stimulating energy in which an active reaction container is filled with a reaction mixture, the reaction mixture comprising said solid pharmaceutical composition. Optionally, in the mechanochemical process at least one solid catalytically active compound is used. Optionally, the solid compound composition is being brought in operative contact with at least a part of the active reaction container and then - optionally also - in contact with the at least one solid catalyst.

In essence, the invention thus also (in its origins) refers to a mechanochemical process to convert at least a part of one or more solid chemical substances or mixture thereof into the respective transformation products, wherein the process is being accomplished with chemically stimulating energy, in which an active reaction container is filled with a reaction mixture, the reaction mixture comprising said solid compound composition.

In a preferred embodiment of the mechanochemical process according to the invention the process is comprising at least one of the following aspects: converting at least a part of one or more solid pharmaceutical compositions, which comprises at least one active pharmaceutical ingredient, into the respective degradation products, the process being accomplished with chemically stimulating energy, preferably with the reaction mixture comprising said solid pharmaceutical composition; AND/OR

- wherein said chemically stimulating energy is kinetic energy produced by at least one ball mill, AND/OR in which an active reaction container being a ball mill is used under specific temperature ranges and gas-phase conditions, preferably including atmospheric conditions, inert gases like nitrogen or other inert gases, or oxygen, and/or using optimized time intervals in the range of 10 minute to 360 minutes.

In a preferred embodiment of the mechanochemical process according to the invention the process is a substantially solvent-free process, more precisely in this residual solvents, crystalline solvates, water content as residual water or bound as hydrates comprised in the composition are not meant by the feature "solvent-free", thus meaning that a "substantially solvent-free process" is a process that is substantially free from additional solvent or solvent added during or before the process). In a preferred embodiment of the mechanochemical process according to the invention the reaction mixture comprising said solid compound composition is substantially solvent- free. More precisely in this, residual solvents, crystalline solvates, water content as residual water or bound as hydrates comprised in the composition are not meant by the feature "solvent-free", thus meaning that a "substantially solvent-free process" is a process that is substantially free from additional solvent or solvent added during or before the process)

In a preferred embodiment of the mechanochemical process according to the invention the solid chemical substances or mixture thereof are a solid compound composition, and/or the respective transformation products are respective degradation products, and/or the solid compound composition is being brought in operative contact with at least a part of the active reaction container and/or

In a preferred embodiment of the mechanochemical process according to the invention, the reaction mixture comprises also at least one solid catalyst, preferably wherein the solid compound composition is being brought in operative contact with at least a part of the active reaction container and also in contact with the at least one solid catalyst.

In a most preferred embodiment of the mechanochemical process according to the invention, the process according to the invention is a substantially solvent-free process, wherein the reaction mixture - being substantially solvent-free - comprises also at least one solid catalyst, wherein the solid compound composition is being brought in operative contact (e.g. applying mechanochemical energy) with at least a part of the active reaction container and also in contact with the at least one solid catalyst.

In a very preferred embodiment of the invention, the invention is drawn to a mechanochemical process using catalytically active compounds with at least one of activities comprising alkaline, acidic, or oxidative properties bound on an organic or inorganic carrier system for simulating and predicting the transformation in quality relevant degradation products of a solid active pharmaceutical ingredient as such or in pre- formulated or formulated dosage forms in a matrix composition of excipients or as binary or multiple mixtures of active pharmaceutical ingredient in the presence of one or more intended excipients used for oral final dosage forms by mixing the carrier bound catalytic system (solid catalytically active compound) in different stoichiometric ratios together with the active pharmaceutical ingredient, mixtures of two or more active pharmaceutical ingredients and/or as pre-formulated or formulated dosage form in the presence with one or more excipients using ball milling systems for energy transfer under specific temperature ranges and gas-phase conditions (including atmospheric conditions, inert gases like nitrogen or other inert gases, or oxygen) using optimized time intervals in the range of 1 minute to 240 minutes so far only obtainable under real-time conditions in the range of 6 to 60 months.

In a further very preferred aspect, the invention is drawn to a process simulating solid state reactions, interactions, degradations and transformations of single compounds and compound mixtures into their respective solid state reaction, interaction, degradation and/or transformation products with or without solid state catalysts under mechano-activation at accelerated conditions to evaluate critical quality attributes of mentioned compounds. In preferred embodiments the compound/s is/are an active pharmaceutical ingredient s (APIs) and excipients. The aim of this process is to evaluate stability of compounds and mixtures. In a further preferred aspect the mechano-activation is done by ball milling. In another further preferred aspect the solid state catalysts (e.g. organic and/or inorganic) are fixed on an inert matrix.

The invention shows the major advantage that the process according to the invention mimics the reaction conditions in a solid phase system in a very fast, reliable and effective way, allowing easy to use flexible operations and simulation of various conditions in a highly predictive manner. Thus, it supports faster drug development with optimized outcome and also higher and more precise predictivity and consequently with a lower failure rates.

Thus, it is a major feature of the mechanochemical process of the invention that it allows for simulating and predicting the transformation in quality relevant degradation products of a solid active pharmaceutical ingredient as such or in pre-formulated or formulated dosage forms in a matrix composition of excipients or as binary or multiple mixtures of active pharmaceutical ingredient in the presence of one or more intended excipients used for oral final dosage forms. Such a result was so far only obtainable under real-time conditions in the range of 6 to 60 months. Another aspect of the current invention is drawn to the use of the mechanochemical process according to the invention to determine the (reaction) kinetics of solid state degradations and transformations to obtain a degradation pathway profile of the active pharmaceutical ingredient alone or in combination with one or more of the respective excipients, which could be used to select the type (and also pharmaceutical quality) of excipient as such, the respective pharmaceutical grade and the stoichiometric ratio with respect to the active pharmaceutical ingredient ratio to obtain an optimized stability profile in terms of shelf-life and impurity and degradation profile of the oral dosage form.

The process according to the invention also shows a high degree of flexibility. Although a standard set-up for solid phase experiments (e.g. based on the Design of Experiments (DOE) principles) may be chosen to evaluate the basic (fundamental) properties of a molecule or mixture, a major advantage will be a high flexibility and customized set-up according to the individual compounds and needs.

Variation of solid phase catalyst include:

- neutral, acidic, alkaline (basic), oxidative catalyst,

- variation of strengths (e.g. ratio of resin to catalytic active principle),

- variation of moisture contents (e.g. simulating different humidity conditions according to the harmonized stability guidelines), and/or

- variation of matrices (e.g. resins); and/or

- catalyst/s (more precise "catalytic active principle)" bound on an pjganic__or inorg_anic carrier system (carrier matrices).

Variation of experimental set-up include:

- variation of catalyst,

- variation of energy input (frequency),

- variation of process time,

- variation of conditions (without oxygen, etc.), specifically this variation on the gas- phase conditions would include atmospheric conditions, oxygen, or inert gases like nitrogen or other inert gases like noble gases like argon; and/or

- variation of humidity.

In the current invention a "mechanochemical process" is defined and understood as any chemical process (especially along degradation and/or transformation pathways) in which energy provided to the process - mostly the activation energy - is derived from a mechanical source or process.

In the current invention "solid compound composition" is defined and understood as any solid compound composition, most preferably a solid pharmaceutical composition. This solid pharmaceutical composition preferably comprises at least one API (an active pharmaceutical ingredient), or said in another way is being a solid composition consisting of at least one API. Most preferably the "solid compound composition" is a "solid pharmaceutical composition". In the current invention "solid pharmaceutical composition" is defined and understood in a preferred mode as comprising at least one API (active pharmaceutical ingredient) and it might contain at least one pharmaceutical excipient. Thus, the solid pharmaceutical composition comprises the pharmaceutical active ingredient (API) as such and/or in combination with excipients as binary or tertiary mixtures or in the final solid dosage form after the drug product manufacturing process including but limited to mixing, compression, coating, drying. In a preferred example it is a solid pharmaceutical composition which is in form of a e.g. tablet, dragees, capsules or a powder.

In the current invention "respective transformation products" is/are defined and understood as the products that will be the result of any transformation process that will occur during or at the end of a transformation process of the respective solid compound composition. This would include polymorphic forms interconversion of of the solid compounds, as well as the respective interaction product which occur due to the interaction of said solid compounds with chemicals in their immediate environment or in solid contact with them or the general reaction products that occur due to the chemical reaction of said solid compounds with chemicals in their immediate environment or in solid contact with them. Alternatively defined, a transformation product is for example the primary or secondary reaction product of an active pharmaceutical ingredient or excipient as a consequence of a transformation process by the formation of reactive intermediates of the active pharmaceutical ingredient and/or excipient by reaction of these reactive intermediates with reaction partners of the composition (active pharmaceutical ingredient or a respective active degradation intermediate or an excipient or an reactive degradation product of an ingredient with each other or any other molecular entity present in the solid phase composition. A transformation product could also be formed by interconversion of different solid forms (solvates, hydrates, polymorphic forms, salts, co-crystals). Preferably though, these "respective transformation products" are "respective degradation products". In the current invention "respective degradation products" is defined and understood as the products that will occur during or at the end of the degradation process of the respective solid compound composition. It would also include polymorphs of the respective solids. In a more narrow definition these are products that are derived from the compounds of said solid compound composition, respective degradation products. Preferably these products are being derived in a chemical reaction under the influence of oxidative conditions, reductive conditions, heat, acidic conditions, or alkaline (also humidic) conditions, preferably oxidative conditions, heat, acidic conditions, or alkaline conditions. Alternatively defined a degradation product is for example the primary or secondary reaction product of an active pharmaceutical ingredient or an excipient as a consequence of a degradation process obtained via intramolecular elimination rearrangement, conjugation, tautomerisation, dimerisation or other reaction pathways.

In the current invention "to convert (or "converting") at least a part of a solid compound composition (or "solid pharmaceutical composition") into the respective degradation products" is defined and understood as that

- 1 to 95 weight-%, 2 to 90 weight-%, 3 to 85 weight-%, 4 to 80 weight-% or 5 - 75 weight-%; or

- 1 to 25 weight-5, 2 to 20 weight-%, or 3 to 15 weight-%; or

- more than 1 weight-%, more than 2.5 weight-%, more than 5 weight-%, more than

7.5 weight-% or more than 10 weight-%

of said "solid compound composition" is converted into said "respective degradation products".

In the current invention "chemically stimulating energy" is defined and understood as any kind of energy that would be sufficient as activation energy to start a chemical reaction process. Most often this is mechanical derived energy (mechano-energy), but this energy could be provided from any source e.g. by raising the temperature or by kinetic energy like that provided by stirring processes, or it could be provided by an ultrasonic source etc. In a preferred embodiment the chemically stimulating energy is kinetic energy, preferably kinetic energy produced by a ball mill. In the process according to the invention the ball mill might then be considered as being the active reaction container and a ball of the ball mill might then be considered as being the part of the active reaction container. In another preferred embodiment the chemically stimulating energy is produced by an ultrasonic source.

In the current invention "solid catalyst" is defined and understood in its broadest sense as a catalyst that is of solid form and retains this solid form during the process according to the invention. The "solid catalyst" is e.g. consisting of a catalytically active principle bound on a solid inorganic and/or organic resin. The expressions "solid catalytically active compound" as well as simply "catalyst" or "solid state catalyst(s)" are used synonymously with "solid catalyst" and are used interchangeable and also fully covered by this definition of "solid catalyst". In a preferred embodiment, the solid catalyst is either fixed to a solid substance or used together with a solid substance. This is the major aspect and the core definition of the solid catalyst is thus the combination of the solid substance acting as a carrier with a catalytically active load, loaded on the carrier which thus together form the "(solid) catalyst". Whenever a ratio is mentioned in connection with catalyst or solid catalyst it is meant the carrier (solid substance) plus (together with) the catalytically active substance(s) as a whole. This solid substance could for example be selected from silica, silicagel or alox (aluminium oxide) but could include other organic polymers being e.g. organic catalytic matrices. The catalysts are preferably selected from acidic solid phase catalysts, alkaline (basic) solid phase catalysts, or oxidative solid phase catalysts. Most preferably the acidic solid phase catalysts are selected from silica gel, sulfuric acid being absorbed on silica gel, trifluoro sulfonic acid absorbed on silica gel. It also includes in general organic and inorganic acids as HCI, H ₂ S0 ₄ , sulfonic acids, halogenic Acidic acids, Bronsted acids, Lewis acids etc. In another most preferable example the alkaline (basic) solid phase catalysts is selected from alox, K ₂ C0 ₃ or DABCO (1 ,4-diazabicyclo[2.2.2]octane). Other alkaline (basic) solid phase catalysts seem to also be very beneficial. In another most preferable example the oxidative solid phase catalysts being selected from KMn0 ₄ on silica or alox, Na ₂ Cr0 ₇ on silica or alox, oxone or Jacobsen metal catalysts. In the definition the catalyst is either fixed to a solid substance or used together with a solid substance, preferably this comprises a metal. There, the solid substance might be selected from silica, silicagel or alox (aluminium-oxide) and also the metal might be selected from Fe, K, Cr, Mn, Co, Na. In examples of the "solid catalyst" is selected from Fe(ll)(BF ₄ ) ₂ , KCr0 ₄ , Mn0 ₂ , Fe ₂ 0 ₃ , CoO, KMn0 ₄ , NaCr ₂ 0 ₇ , or NaCr ₂ 0 ₇ · 2 H ₂ 0. It might be selected from Fe(ll)(BF ₄ ) ₂ on silicagel, KCr0 ₄ on alox, Mn0 ₂ on silicagel, Fe ₂ 0 ₃ on silicagel, CoO on silicagel, KMn0 ₄ on alox, NaCr ₂ 0 ₇ on alox, NaCr ₂ 0 ₇ on silica, NaCr ₂ 0 ₇ · 2 H ₂ 0 + alox, or NaCr ₂ 0 ₇ · 2 H ₂ 0 + silicagel. Most preferably this "solid catalyst" might be KMn0 ₄ on silica (dry), KMn0 ₄ on silica (39% H ₂ 0), KMn0 ₄ on aluminium oxide (dry) or Silica sulfuric acid.

In the current invention "active reaction container" is defined and understood as any container able to allow said "mechanochemical process" to proceed within its physical boundaries, and/or able to contain said "reaction mixture" and/or able to transfer or allowing transferal of said "chemically stimulating energy" to the mechanochemical process and/or "reaction mixture". Preferably, the "active reaction container" is a container able to allow said "mechanochemical process" to proceed within its physical boundaries, to contain said "reaction mixture" and to transfer or allowing transferal of said "chemically stimulating energy" to the mechanochemical process and/or "reaction mixture". One of the most preferred examples of such an "active reaction container" would be a ball mill or potentially a mixer.

In the current invention "substantially solvent-free" is defined and understood as a composition/mixture comprising no or close to no solvent ("close to no" meaning less than 1 weight-% or < 0.5 weight-% solvent per weight of the solid like said reaction mixture, said solid compound composition and/or said solid catalyst). More precisely in this, residual solvents, crystalline solvates, water content as residual water or bound as hydrates comprised in the composition are not meant by the feature "solvent-free", thus meaning that a "substantially solvent-free process" is a process that is substantially free from additional solvent or solvent added during or before the process).

In the current invention "substantially solvent-free process" is defined and understood as a process in which each composition or mixture comprises no or close to no solvent ("close to no" meaning less than 1 weight-% or < 0.5 weight-% solvent per weight of the solid like said reaction mixture, said solid compound composition and/or said solid catalyst). More precisely in this, residual solvents, crystalline solvates, water content as residual water or bound as hydrates comprised in the composition are not meant by the feature "solvent- free", thus meaning that a "substantially solvent-free process" is a process that is substantially free from additional solvent or solvent added during or before the process).

In the current invention "operative contact" is defined and understood as a physical contact between said "solid compound composition" and at least a part of said "active reaction container" during the process (during operation of the container") e.g. by mixing and applying chemically stimulating energy. In one preferred embodiment in which the "active reaction container" is a ball mill it signifies the physical contact between the solid compound composition with a ball of the ball mill or with a pedal or a blade if the container is a mixer. The mechanochemical process according to the invention wherein the reaction mixture consists of said solid compound composition and at least one solid catalyst, the catalyst optionally being either fixed to a solid substance or used together with a solid substance, the solid substance optionally being either silica, silicagel or alox; and/or

In a preferred embodiment of the mechanochemical process according to the invention, the reaction mixture comprises at least one solid catalyst, and/or the chemically stimulating energy is kinetic energy produced by at least one ball mill being the abovementioned active reaction container and a ball of the ball mill being the abovementioned part of the active reaction container, or the chemically stimulating energy is produced by an ultrasonic source, and/or the contact is occurring at a temperature and for a length of time sufficient to convert at least a part of the solid compound composition /preferably via the induction of the transformation and/or degradation pathway in the respective transformation and/or degradation products.

In a preferred embodiment of the mechanochemical process according to the invention the contact in the process is occurring at a temperature between 0 and 100°C, preferably between 18 and 95°C, more preferably at room temperature or at a temperature between 40 and 90°C or 60 and 80°C; and/or the contact in the process is occurring at a pressure of between 500 bar and 3000 bar, preferably at atmospheric pressure or at 1013 bar; and /or the contact in the process is occurring for 10 to 600 min, preferably for 30 to 420 min, more preferably for 40 to 360 min.

In a preferred embodiment of the mechanochemical process according to the invention the contact in the process is occurring for 10 to 600 min, preferably for 30 to 420 min, more preferably for 40 to 360 min or for 1 min to 240 min, or for 10 to 360 min.

In a preferred embodiment of the mechanochemical process according to the invention the reaction mixture is achieved by mixing the carrier bound catalytic system (solid catalytically active compound) together with said solid pharmaceutical composition comprising the active pharmaceutical ingredient, mixtures of two or more active pharmaceutical ingredients and/or as pre-formulated or formulated dosage form in the presence with one or more excipients. Preferably, the mixing is done in different stoichiometric ratios, preferably in the range (catalyst:API or solid catalytically active compound:API as weight stoichiometry) selected of from 1 :20 to 20:1 ; or from 1 :15 to 20:1 , or from 1 :20 to 15:1 or from 1 :15 to 15:1 or from 1 :12.5 to 12.5:1 or from 1 :10 to 15:1 , or from 1 :15 to 10:1 or from 1 :10 to 10:1 or from 1 :5 to 5:1 . Weight stoichiometry being understood as the weight ratio between the catalyst or solid catalytically active compound and the API.

In a preferred embodiment of the mechanochemical process according to the invention the solid compound composition is a solid pharmaceutical composition comprising at least one API (a compound being an active pharmaceutical ingredient), or a solid composition consisting of at least one API, preferably is a solid pharmaceutical composition comprising at least one API and at least one pharmaceutical excipient, the solid pharmaceutical composition preferably being in form of a tablet, dragees, capsules or a powder.

In a preferred embodiment of the mechanochemical process according to the invention the solid compound composition is a solid pharmaceutical composition consisting of at least one API and at least one pharmaceutical excipient, the solid pharmaceutical composition preferably being in form of a tablet, dragees, capsules or a powder.

In a preferred embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is selected from acidic solid phase catalysts (solid catalytically active compounds), basic (alkaline) solid phase catalysts (solid catalytically active compounds), or oxidative solid phase catalysts (solid catalytically active compounds), with preferably the acidic solid phase catalysts (solid catalytically active compounds) being selected from silica gel, sulfuric acid being absorbed on silica gel, trifluoro sulfonic acid absorbed on silica gel; and/or the basic (alkaline) solid phase catalysts (solid catalytically active compounds) being selected from alox, K ₂ C0 ₃ or DABCO (1 ,4-diazabicyclo[2.2.2]octane); and/or the oxidative solid phase catalysts (solid catalytically active compounds) being selected from KMn0 ₄ on silica or alox, Na ₂ Cr0 ₇ on silica or alox, oxone or Jacobsen metal catalysts (solid catalytically active compounds).

In a preferred embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is either fixed to a solid substance (thus forming a unit called solid catalytically active compound) or used together with a solid substance and/or is comprising a metal, with the solid substance preferably being selected from silca, silicagel or alox (aluminium-oxide) and the metal preferably being selected from Fe, K, Cr, Mn, Co, Na.

More preferably in a preferred embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is selected from Fe(ll)(BF ₄ ) ₂ , KCr0 ₄ , Mn0 ₂ , Fe ₂ 0 ₃ , CoO, KMn0 ₄ , NaCr ₂ 0 ₇ , or NaCr ₂ 0 ₇ · 2 H ₂ 0; most preferably the at least one catalyst (solid catalytically active compound) is selected from Fe(ll)(BF ₄ ) ₂ on silicagel, KCr0 ₄ on alox, Mn0 ₂ on silicagel, Fe ₂ 0 ₃ on silicagel, CoO on silicagel, KMn0 ₄ on alox, NaCr ₂ 0 ₇ on alox, NaCr ₂ 0 ₇ on silica, NaCr ₂ 0 ₇ · 2 H ₂ 0 + alox, or NaCr ₂ 0 ₇ · 2 H ₂ 0 + silicagel.

Most preferably in a preferred embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is selected from KMn0 ₄ on silica (dry), KMn0 ₄ on silica (39% H ₂ 0), KMn0 ₄ on aluminium oxide (dry) or Silica sulfuric acid. In another embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is selected from fresh alkaline reagents that could be used to initiate alkaline degradation. Preferably this could be selected from NaOCH ₃ , Na ₂ C0 ₃ , CsC0 ₃ , calcite, or hydrotalcite. In a preferred embodiment of the mechanochemical process according to the invention the at least one catalyst (solid catalytically active compound) is selected from the reaction mixture consists of said solid compound composition and at least one solid catalyst (solid catalytically active compound).

In this preferred embodiment of the mechanochemical process according to the invention in the directly preceding paragraph, the catalyst (solid catalytically active compound) optionally is either fixed to a solid substance (thus forming a new solid catalytically active compound) or used together with a solid substance, the solid substance optionally being either silica, silicagel or alox; and/or said solid compound composition is substantially solvent-free; and/or said catalyst (solid catalytically active compound) and the optional solid substance are substantially solvent-free.

In a preferred embodiment of the mechanochemical process according to the invention the respective transformation (or degradation) products are products derived from the compounds of said solid compound composition, the respective transformation (or degradation) products preferably being derived in a chemical reaction under the influence of oxidative conditions, reductive conditions, heat, acidic conditions, or alkaline conditions, preferably the respective transformation (or degradation) products preferably being derived in a chemical reaction under the influence of oxidative conditions, heat, acidic conditions, or alkaline conditions. In a preferred embodiment of the mechanochemical process according to the invention the compounds or components used in said mechanochemical process do not necessarily contain a catalyst. Thus especially, the reaction mixture does not comprise any catalyst. This is sometimes advantageous as in some cases differentiation of transformation and/or degradation processes might relate to the presence of the catalytically active principles bound on their respective inorganic and/or organic resins and the respective degradation and/or transformation pathways induced only by the presence of the inoerganic and/or organic resins or without any catalyst (solid catalytically active compound).

Another aspect of the current invention is drawn to an analytical process in which the composition mixture remaining in the active reaction container (or in the ball mill) at the end of a process according to the mechanochemical process according to the invention is analyzed by removing a sample from said composition mixture remaining in the active reaction container, optionally removing the catalyst/s (solid catalytically active compound/s) from said sample, and analysis of the remaining sample material according to a standard analytical method for its content including potentially generated transformation (or degradation) products from the process according to the mechanochemical process according to the invention. In a preferred embodiment of the analytical process according to the invention the catalyst (solid catalytically active compound) is removed by filtering after the sample is dissolved in a solvent, preferably in an organic solvent like THF, and/or wherein the standard analytical method is GC-MS or HPLC-MS, and/or wherein the identified transformation (or degradation) products are compared to the database of known compounds.

In another preferred - potentially related - embodiment of the analytical process according to the invention the analysis is done by an automatized step, preferably by High Throughput Analysis or by the use of an IR sensor. More preferably this might include HPLC UPLC mit UV DAD, MS spectroscopy, IR- und Raman spectroscopy, UV- spectroscopy and combined analytical processes and detection-systems.

Another aspect of the current invention is drawn to a transformation (or degradation) product derived by the mechanochemical process according to the mechanochemical process according to the invention and identified by the analytical process according to the invention, wherein the transformation (or degradation) product is identified as not being part of the database of known compounds identified according to the immediately preceding paragraph. Another aspect of the current invention is drawn to a medicament comprising at least one transformation (or degradation) product derived from the mechanochemical process according to the invention. In a preferred embodiment of the medicament it is comprising more than one of the transformation (or degradation) products.

Another aspect of the current invention is drawn to an analytical kit comprising an assortment of at least three separate catalyst-containers A-C, with catalyst-container A comprising an acidic solid phase catalysts (solid catalytically active compounds), catalyst- container B comprising a basic (alkaline) solid phase catalysts (solid catalytically active compound), and catalyst-container C comprising an oxidative solid phase catalysts (solid catalytically active compound), for use in the mechanochemical process according to the invention and/or the analytical process according to the invention.

Another aspect of the current invention is drawn to a device prepared to be used in a mechanochemical process according to the invention. This equipment may take the form of a machine which would a) include an active reaction container being capable of being filled with said reaction mixture and b) a source for applying said chemically stimulating energy which could optionally be included/integrated in said active reaction container. This device may preferably be prepared to accept said catalysts (solid catalytically active compounds), more preferably adapted to accept one or more catalyst-containers, like catalyst-containers A-C above.

Preferably in the analytical kit of the current invention described in the immediately preceding paragraph the acidic solid phase catalyst/s (solid catalytically active compounds) being selected from silica gel, sulfuric acid being absorbed on silica gel, trifluoro sulfonic acid absorbed on silica gel; and/or the basic (alkaline) solid phase catalyst s (solid catalytically active compounds) being selected from alox, K ₂ C0 ₃ or DABCO (1 ,4-diazabicyclo[2.2.2]octane); and/or the oxidative solid phase catalyst/s (solid catalytically active compounds) being selected from KMn0 ₄ on silica or alox, Na ₂ Cr0 ₇ on silica or alox, oxone or Jacobsen metal catalysts (solid catalytically active compounds).

Another aspect of the current invention is drawn to the use of the mechanochemical process according to the invention to determine one or more of a) a potential safety risk by, b) the potential shelf life of, c) the fitting excipients for, d) a potential combination partner for the solid compound composition converted by the process into the respective transformation or degradation products, and/or e) the synthesis of identified impurities as reference standards.

Figures:

The following is a brief description of the Figures:

Figure 1 :

Figure 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].

Figure 2: Figure 2 shows a HPLC-chromatogram of clopidogrel bisulphate after milling reaction with an acidic solid phase catalyst. Figure 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.

Figure 3:

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

Figure 4:

Figure 4 shows a degradation of clopidogrel with oxidative solid phase catalyst (KMn0 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.

Figure 5:

Figure 5 shows a DSC profile of clopidogrel bisulphate polymorph II

Figure 6:

Figure 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.

Figure 7: Figure 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 Figure 6. Figure 8:

Figure 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.

Figure 9:

Figure 9 shows a sample of clopidogrel bisulphate with alkaline stressor Na ₂ C0 ₃ stored at 40°C/94% RH for 15 days.

Figure 10:

Figure 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..

Figure 11 :

Figure 1 1 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.

Figure 12:

Figure 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.

The invention was further illustrated by Exampl EXAMPLES Example 1 : Proof of Concept

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.

The following analytical methods were implemented. Two solid phase oxidation reactions were prepared. The catalyst used was KMn0 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.

The degradation process is shown in the below structures:

p-methoxybenyzl alcohol p-methoxybenaldehyd

silica

diphenylsulfide diphenylsulfoxide diphenylsulfone 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. diphenylsulfide diphenylsulfone

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

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

KMn0 ₄ on silica (dry)

KMn0 ₄ on silica (39% H ₂ 0)

KMn0 ₄ on aluminium oxide (dry)

Silica sulfuric acid

Example 3: Final experimental set-up of a solid phase prediction platform

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": PCT/EP2017/080275 REPLACEMENT SHEET 2018/0 RD&C

Generation of solid state stress samples.

pH effect Additive pFP Replicate sample numbers

Dark chamber study Light chamber study

HPLC analysis LC-MS HPLC analysis L

1 month 3 months 3.months 1.2 x I0 ⁶ Ix h

fluorescent light arid

200 Wh m ² UV light

Without additive 2,7 3

Acidic Oxalic acid 1.3 3

Alkali -Sodium carbonate 10J }

pH of the microenvironment was cieterniined by the method given by Serajuddin et al, [18],

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

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

10 Figure 2 shows a HPLC-chromatogram of clopidogrel bisulphate after milling reaction with an acidic solid phase catalyst. Figure 2 cl shows, that the acidic degradation product (RT 15 min), that was detected in the literature after incubation of the API with an acidic stress 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 id of the degradation product was confirmed by corresponding retention time and mass spectrum.

Additionally, the quantity of degradation was compared between the conventional forced degradation conditions and the solid phase condi

15 showing a comparable amount after 60 minutes process time already. This is shown Figure 3.

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

Another experiment was set-up with clopidogrel and an oxidative solid phase catalyst (KMn0 ₄ on aluminium oxide, dry) to demons oxidative degradation and time-dependency of degradation mechanism. The result is shown in Figure 4.

Figure 4 shows a degradation of clopidogrel with oxidative solid phase catalyst (KMn0 ₄ on aluminium oxide, dry) with process times between 60 and 300 minutes.

Figure 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. 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.

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

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

Figure 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 Figure 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

To evaluate the reliability and robustness of the analytical method a "mini-validation" with 3 repetitions was performed. Table 1 :

Data on linearity for concentrations between 100 μς/ΓτιΙ. and 1000 μς/ΓτιΙ. clopidogrel bisulphate

Figure 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.

Figure 9 shows a sample of clopidogrel bisulphate with alkaline stressor Na ₂ C0 ₃ stored at 40°C/94% RH for 15 days.

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 Figure 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.

Figure 10 shows an overlay of three injections of the oxidative sample after milling for 60 minutes at 25 Hz. Table 2. Reproducibility of the HPLC method (peak areas of degradation products of 3 repetitions)

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 Figures 1 1 and 12 as well as in Table 3.

Figure 1 1 shows an overlay of acidic solid phase samples of three independent milling experiments after 30 min at 25 Hz.

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

Table 3: Reproducibility test of milling method. Obtained peak areas of degradation products of 3 repetitive milling experiments