Particle size and distribution of polymer for melt extrusion application

Abstract

An extrudable polyvinyl alcohol (PVA) powder with improved flowability containing particles of PVA, which has been cryo-milled, and which has d.sub.50 particle sizes in the range of 45 to 1400 μm; or which has a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, and d.sub.99=300±30 μm; and a powdery composition for the preparation of pharmaceutical formulations which contains the polyvinyl alcohol homogeneously mixed with at least one active pharmaceutical ingredient (API); and a process for producing a solid pharmaceutical dosage form by extruding or forming a homogeneous melt of a mixture of ingredients containing the powdered polyvinyl alcohol and at least one active pharmaceutical ingredient (API), and forming a powder or a molded form.

Claims

1. An extrudable polyvinyl alcohol (PVA) powder with improved flowability, consisting of particles consisting of PVA, which has been cryo-milled, and which has d.sub.50 particle sizes in the range of 45 to 1400 μm.

2. An extrudable polyvinyl alcohol (PVA) powder with improved flowability, consisting of particles consisting of PVA, which has been cryo-milled, and which has a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, and d.sub.99=300±30 μm.

3. The polyvinyl alcohol according to claim 1, which has been extruded.

4. The polyvinyl alcohol according to claim 1 having a viscosity ≤40 mPa.Math.s, the viscosity being measured on 4% w/v aqueous solution at 20° C. DIN 53015.

5. The polyvinyl alcohol according to claim 1, which is selected from the group consisting of PVA 3-88, PVA 4-88, PVA 5-74, PVA 5-88, PVA 8-88, and PVA 18-88.

6. The polyvinyl alcohol according to claim 1, which is capable of providing uninterrupted feeding and dosing during processing.

7. A powdery composition for the preparation of pharmaceutical formulations, comprising the polyvinyl alcohol according to claim 1 homogeneously mixed with at least one active pharmaceutical ingredient (API).

8. The powdery composition according to claim 7, comprising at least one additive selected from the group consisting of plasticizers, surface active materials, antioxidants, stabilizing agents, solubility-enhancing agents, pH control agents and flow regulators.

9. The powdery composition according to claim 7, which is a pharmaceutical grade powder comprising one or more further excipient(s) with d.sub.50 particle sizes in the range of 45 μm to 1400 μm.

10. The powdery composition according to claim 7, which is a pharmaceutical grade powder comprising one or more further excipient(s) having a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, d.sub.99=300±30 μm.

11. A process for producing a solid pharmaceutical dosage form, comprising extruding or forming a homogenous melt of a mixture of ingredients comprising the cryo-milled powdered polyvinyl alcohol according to claim 1 and at least one active pharmaceutical ingredient (API), and forming a powder or a molded form.

12. The process according to claim 11, comprising continuously and evenly feeding the mixture of ingredients into a feeder line of an extruder, processing said mixture to a homogeneous melt, and then shaping the melt.

13. A process for producing a solid pharmaceutical dosage form according to claim 11, comprising a) cryo-milling the polyvinyl alcohol (PVA) to a powder having d.sub.50 particle sizes in the range of 45 to 1400 μm, and b) homogeneously mixing the resultant powder with at least one active pharmaceutical ingredient, and optionally with at least one additive selected from the group consisting of plasticizers, surface active materials, antioxidants, stabilizing agents, solubility-enhancing agents, pH control agents and flow regulators, thereby forming a powdery composition, and c) evenly feeding said composition into a feeder line of an extruder followed by processing to a homogeneous melt, and shaping.

14. A process according to claim 11, wherein the polyvinyl alcohol (PVA) is cryo-milled to a powder having a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, and d.sub.99=300±30 μm.

15. A process according to claim 11, wherein the polyvinyl alcohol (PVA) has a viscosity ≤40 mPa.Math.s, the viscosity being measured on 4% w/v aqueous solution at 20° C. DIN 53015, and which is cryo-milled to a powder having a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, and d.sub.99=300±30 μm, and wherein optionally the particle size distribution is adjusted by combining respective sieve fractions.

16. A process according to claim 11, wherein the polyvinyl alcohol (PVA) is selected from the group consisting of PVA 3-88, PVA 4-88, PVA 5-74, PVA 5-88, PVA 8-88, and PVA 18-88, and which is cryo-milled to a powder having a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, and d.sub.99=300±30 μm, and wherein optionally the particle size distribution is adjusted by combining respective sieve fractions.

17. A solid pharmaceutical dosage form that has been obtained by the process according to claim 11.

18. A process for producing a solid pharmaceutical dosage form according to claim 12, comprising a) cryo-milling the polyvinyl alcohol (PVA) to a powder having d.sub.50 particle sizes in the range of 45 to 1400 μm, and b) homogeneously mixing the resultant powder with at least one active pharmaceutical ingredient, and optionally with at least one additive selected from the group consisting of plasticizers, surface active materials, antioxidants, stabilizing agents, solubility-enhancing agents, pH control agents and flow regulators, thereby forming a powdery composition, and c) evenly feeding said composition into a feeder line of an extruder followed by processing to a homogeneous melt, and shaping.

19. The polyvinyl alcohol according to claim 1, which has particle sizes in the range of 50 to 300 μm.

20. The polyvinyl alcohol according to claim 1, which has a particle size distribution of d.sub.10=20±10 μm, d.sub.50=70±10 μm and d.sub.90=200±30 μm.

21. The polyvinyl alcohol according to claim 1, which has a particle size distribution of d.sub.10=17.25±10 μm, d.sub.50=63.74±10 μm and d.sub.90=169.91±30 μm.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: shows a NMR spectrogram of 20 mg indomethacin and 20 mg maleic acid in DMSO-d6

(2) FIG. 2: shows the volume-particle size plot of PVA 4-88, having a particle size distribution of D.sub.10=6.2 μm/D.sub.50=27.99 μm/D.sub.90=54.76 μm

(3) FIG. 3: shows the differences in the angles of repose of PVA powders of Groups A, B and C without the addition of any API

(4) FIG. 4a: shows the feeding performance of PVA powder of Group A without API. The feeding is not uniform and shows irregularities.

(5) FIG. 4b: shows the feeding performance of PVA powder of Group A with 30% by weight of API. The feeding is not uniform and shows comparable irregularities as the feeding of the pure powder.

(6) FIG. 4c: shows the feeding performance of PVA powder of Group B without API. The feeding is very uniform.

(7) FIG. 4d: shows the feeding performance of PVA powder of Group B with 30% by weight of API. The feeding is also very uniform and is comparable to the feeding of the pure powder of Group B.

(8) FIG. 5: shows the volume-particle size plot of PVA 4-88, having the advantageous particle size distribution of D.sub.10=17.25 μm/D.sub.50=63.74 μm/D.sub.90=169.91 μm.

DETAILED DESCRIPTION OF THE INVENTION

(9) While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides more applicable inventive concepts than described here in detail. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.

(10) To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.

(11) As used herein, the term “a homogenous melt, or mixture or form” refers to the various compositions that can be made by extruding the made-up source material, which is prepared by milling and combining selected sieve fractions.

(12) As used herein, the term “heterogeneously homogeneous composite” refers to a material composition having at least two different materials that are evenly and uniformly distributed throughout the volume and which are prepared of the one or more APIs and the one or more pharmaceutically acceptable excipients, including a pretreated PVA into a composite.

(13) As used herein, “bioavailability” is a term meaning the degree to which a drug becomes available to the target tissue after being administered to the body. Poor bioavailability is a significant problem encountered in the development of pharmaceutical compositions, particularly those containing an active ingredient that is not highly soluble.

(14) As used herein, the phrase “pharmaceutically acceptable” refers to molecular entities, compositions, materials, excipients, carriers, and the like that do not produce an allergic or similar untoward reaction when administered to humans in general.

(15) As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable materials” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art.

(16) The API (active pharmaceutical ingredient) may be found in the form of one or more pharmaceutically acceptable salts, esters, derivatives, analogs, prodrugs, and solvates thereof. As used herein, a “pharmaceutically acceptable salt” is understood to mean a compound formed by the interaction of an acid and a base, the hydrogen atoms of the acid being replaced by the positive ion of the base.

(17) As used herein, “poorly soluble” refers to having a solubility means the substance needs 100 ml solvent to dissolve 1 g substance.

(18) For the characterizing particle sizes “mean” or “average particle sizes” (d.sub.50) are given. These values are assessed by means of sieve analysis using wire mesh plates. Sieve plates are arranged from largest aperture to smallest, and the particle size is assessed based on proportion of material caught at each level. All sieve plates have apertures with square cross sections. The mean particle size (d.sub.50) is then calculated from the sieving results. d.sub.50 is defined as the equivalent diameter where 50% of the mass (of particles) of the sampled powder has a smaller diameter, and thus 50% of the material remains coarser. d.sub.50 can therefore be described as the average particle size.

(19) As used herein, “derivative” refers to chemically modified inhibitors or stimulators that still retain the desired effect or property of the original API. Such derivatives may be derived by the addition, removal, or substitution of one or more chemical moieties on the parent molecule. Such moieties may include, but are not limited to, an element such as a hydrogen or a halide, or a molecular group such as a methyl group. Such a derivative may be prepared by any method known to those of skill in the art. The properties of such derivatives may be assayed for their desired properties by any means known to those of skill in the art. As used herein, “analogs” include structural equivalents or mimetics.

(20) A variety of administration routes are available for delivering the APIs to a patient in need. The particular route selected will depend upon the particular drug selected, the weight and age of the patient, and the dosage required for therapeutic effect. The pharmaceutical compositions may conveniently be presented in unit dosage form. The APIs suitable for use in accordance with the present disclosure, and their pharmaceutically acceptable salts, derivatives, analogs, prodrugs, and solvates thereof, can be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent, or carrier selected with regard to the intended route of administration and standard pharmaceutical practice.

(21) The APIs may be used in a variety of application modalities, including oral delivery as tablets, capsules or suspensions; pulmonary and nasal delivery; topical delivery as emulsions, ointments or creams; transdermal delivery; and parenteral delivery as suspensions, microemulsions or depot. As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, or infusion routes of administration.

(22) The solution agent used in the solution can be an aqueous such as water, one or more organic solvents, or a combination thereof. When used, the organic solvents can be water miscible or non-water miscible. Suitable organic solvents include but are not limited to ethanol, methanol, tetrahydrofuran, acetonitrile, acetone, tert.-butyl alcohol, dimethyl sulfoxide, N,N-dimethyl formamide, diethyl ether, methylene chloride, ethyl acetate, isopropyl acetate, butyl acetate, propyl acetate, toluene, hexanes, heptane, pentane, and combinations thereof.

(23) The excipients and adjuvants that may be used in the presently disclosed compositions and composites, while potentially having some activity in their own right, for example, antioxidants, are generally defined for this application as compounds that enhance the efficiency and/or efficacy of the effective ingredients. It is also possible to have more than one effective ingredient in a given solution, so that the particles formed contain more than one effective ingredient.

(24) As stated, excipients and adjuvants may be used to enhance the efficacy and efficiency of the APIs.

(25) Thermal binders may also be used in the presently disclosed compositions and composites.

(26) Depending on the desired administration form the formulations can be designed to be suitable in different release models, which are well known to the skilled person, as there are: immediate, rapid or extended release, delayed release or for controlled release, slow release dosage form or mixed release, including two or more release profiles for one or more active pharmaceutical ingredients, timed release dosage form, targeted release dosage form, pulsatile release dosage form, or other release forms.

(27) The resulting composites or compositions disclosed herein may also be formulated to exhibit enhanced dissolution rate of a formulated poorly water soluble drug.

(28) The United States Pharmacopeia-National Formulary mandates that an acceptable polyvinyl alcohol for use in pharmaceutical dosage forms must have a percentage of hydrolysis between 85 and 89%, as well as a degree of polymerization between 500 and 5000. The degree of polymerization (DM) is calculated by the equation:
DM=(Molar Mass)/((86)−(0,42(the degree of hydrolysis)))

(29) The European Pharmacopoeia mandates that an acceptable polyvinyl alcohol for use in pharmaceutical dosage forms must have an ester value no greater than 280 and a mean relative molecular mass between 20,000 and 150,000. The percentage of hydrolysis (H) can be calculated from the following equation:
H=((100−(0,1535)(EV))/(100−(0,0749)(EV)))×100

(30) Where EV is the ester value of the polymer. Thus, only polymers with a percentage of hydrolysis greater than 72.2% are acceptable according to the European Pharmacopoeia monograph.

(31) As already mentioned above, commercial polyvinyl alcohols in particulate form have poor flow behavior, especially if they are characterized by low viscosities (measured in a 4% aqueous solution at 20° C.). Accordingly, these powders have no continuous trouble-free flow. However, the latter is a prerequisite for a uniform feed to the processing of such powder materials.

(32) Theoretically, powders, whose particle shapes are rather round and spherical, in general have the best flow behavior. Accordingly, in the past, attempts have been made to produce polyvinyl alcohol powders already directly by its synthesis with spherical particles. For example, from DE 38 11 201A a method is known for producing of spherical particles by suspension polymerization. However, this reaction requires a special adjustment of the reaction conditions. In addition, this reaction has to be followed by a hydrolysis reaction. With different particle sizes, it is difficult to achieve a uniform degree of hydrolysis of the polymer particles. By this method, polyvinyl alcohol powders are produced having viscosities of 80 mPa.Math.s or higher.

(33) Therefore, for the production of polyvinyl alcohol powders, which are comparable with those of the present invention, this method provides no alternative, especially as here PVA grades are desirable having viscosities of ≤40 mPa.Math.s.

(34) Now, it was found that these polyvinyl alcohol grades having viscosities of ≤40 mPa.Math.s are also suitable to be manufactured by melt extrusion if they are pretreated as disclosed in the following and a homogenously dispersed solid solution of pharmaceutical active ingredient in polyvinyl alcohol can be produced by extrusion and the applied PVA powder can be fed without problems into the feeder.

(35) In this way also poorly soluble pharmaceutical active ingredients (from BCS class II and IV) can be homogeneously mixed with PVA to build a solid dispersion. Furthermore, it was found by experiments that PVA in the different degrees of hydrolysis having viscosities of ≤40 mPa.Math.s can be homogeneously mixed by melt extrusion with poorly soluble active ingredients, especially with PVA that is in accordance with the European Pharmacopoeia monograph and which is a pharmaceutically acceptable PVA with hydrolysis grades greater than 72.2%, and especially which includes grades of PVA that are pharmaceutically acceptable by either the USP (hydrolysis between 85-89%) or Ph. Eur. (hydrolysis grades greater than 72.2%). These PVA qualities have a molecular weight in the range of 14,000 g/mol to 250,000 g/mol.

(36) Powdery compositions according to the invention may comprise at least a biologically active ingredient combined with a PVA that is pharmaceutically acceptable, which is combined with another pharmaceutically acceptable polymer. Such pharmaceutically acceptable polymer can also be selected from the group of hydrophilic polymers and can be a primary or secondary polymeric carrier that can be included in the composition disclosed herein and including polyethylene-polypropylene glycol (e.g. POLOXAMER™), carbomer, polycarbophil, or chitosan, provided that they are as free-flowing powder and are extrudable polymers. Hydrophilic polymers for use with the present invention may also include one or more of hydroxypropyl methylcellulose, carboxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylcellulose, natural gums such as gum guar, gum acacia, gum tragacanth, or gum xanthan, and povidone. Hydrophilic polymers also include polyethylene oxide, sodium carboxymethylcellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, carboxypolymethylene, polyethylene glycol, alginic acid, gelatin, polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazolidines, poly(hydroxyalkylcarboxylic acids), carrageenate alginates, carbomer, ammonium alginate, sodium alginate, or mixtures thereof.

(37) In general, it must be considered that there are special requirements for polymers used as hot melt extrusion excipients:

(38) The polymer must be thermoplastic, must have a suitable glass transition temperature and a high thermal stability. The polymer must have no toxic properties and must have a high biocompatibility, etc. Therefore, pharmaceutical grades of polyvinyl alcohol (PVA), which are chosen here for the preparation of formulations comprising active ingredients by hot melt extrusion, are those having a low viscosity.

(39) Polyvinyl alcohol (PVA) is a synthetic polymer, which is produced by polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer. As already mentioned above, chemical and physical properties of polyvinyl alcohol, such as viscosity, solubility, thermal properties, etc. are very depending on its degree of polymerization, chain length of PVA polymer, and the degree of hydrolysis.

(40) PVA can be used for the production of different formulations for various modes of administration to treat a variety of disorders. Accordingly, PVA is processed in a wide range of pharmaceutical dosage forms, including ophthalmic, transdermal, topical, and especially, oral application forms.

(41) As mentioned above, it is for the successful industrial processing of a solid in an extrusion process also necessary that a uniform continuous metering is possible in the feed of the extruder.

(42) We have found, that for this purpose, the solid must have suitable particle characteristics, including appropriate particle sizes, and flowability or fluidity.

(43) It was also found through the experiments, that by the inventive pretreatment of appropriate commercially available PVA, optionally by blending with suitable ingredients, a stable product is obtained, which may be prepared as a ready-to-use product. Such a product can easily be loaded into the feeder of the extruder without any interruption and it makes the extrusion process feasible although a PVA is used as an excipient having a low viscosity of ≤40 mPa.Math.s.

(44) It was found, that an easily extrudable product can be obtained, when a commercially available PVA with pharma grade and low viscosity of ≤40 mPa.Math.s is milled into fine powder and blended with ingredients.

(45) The resulting mixture can be fed continuously without problems and without any halt into the feeder of an extruder. Thus, the pretreatment of the applied PVA makes, that the extrusion process is feasible in a simple manner. In addition, it has been found, that not only the milling to a fine powder improves the uniform feeding of the PVA powder into the feeder of the extruder. Surprisingly, further significant improvement in the flowability of the milled polymer powder is achieved by sieving the milled polymer into various sieve fractions, and subsequent combining certain sieve fractions having specific grain sizes with each other. In summary, clearly defined particle sizes and size distributions result in PVA powders with significantly improved flowability and thus in an improved processability of the received PVA powders.

(46) It was found, that milled polyvinyl alcohol powders of pharmaceutical grade to a powder as characterized above and having particle sizes in the range of 45 to 1400 μm, preferably in the range of 45 to 1000 μm, most preferred in the range of 50-300 μm show improved flowabilities.

(47) In particular, these powders exhibit improved flow properties when the particle size distribution is in the range of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, d.sub.99=300±30 μm, namely when solid polyvinyl alcohol (PVA) having pharmaceutical grade is applied which is characterized having a viscosity ≤40 mPa.Math.s, the viscosity being measured on 4% aqueous solution at 20° C. DIN 53015. In this case very particularly preferred is the use of polyvinyl alcohol (PVA) having pharmaceutical grade, selected from the group: PVA 3-80, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA23-88, PVA 26-80, PVA 26-88, PVA28-99, PVA 30-98, PVA 30-92, PVA 32-88, PVA 40-88, most preferred from the group: PVA 3-88, PVA 4-88, PVA 5-74, PVA 5-88, PVA 8-88, and PVA 18-88, which is milled to a powder having a particle size distribution of d.sub.10=20±10 μm, d.sub.20=30±10 μm, d.sub.50=70±10 μm, d.sub.90=200±30 μm, d.sub.99=300±30 μm, and wherein optionally the particle size distribution is adjusted by combining respective sieve fractions.

(48) Powders, comprising particles larger than in the range of about 1400 μm, cannot be fed into the feeder, because of a lack of homogeneity of the mixture of ingredients and PVA particles, especially because they tend to stick and to agglomerate, but also they tend to separate out, because of the different sized ingredients that segregate.

(49) A particularly troublesome problem in this case is that pharmaceutical active ingredients (APIs), which have smaller particle diameters, segregate during feeding, and in the following it is not any more possible to achieve a homogeneous distribution in the carrier polymer during extrusion.

(50) Additionally, it is very difficult to control the feeding rate of the mixture with large polyvinyl alcohol particles. The particle size and distribution of polymer powders used as carrier is a significant parameter to influence the feasibility and accuracy of extruder feeding. On the other side, particle sizes lower than in the range given above, especially particle sizes lower than 45 μm, lead to issues of lack of flowability and feeder blocking. Therefore, in connection with the experiments carried out, it was found that it is advantageous to define a suitable particle size distribution for PVA, if it shall be applied as excipients in the production of pharmaceutical formulations, which are prepared by hot melt extrusion.

(51) Here it has to be considered, that a continuous extrusion is only possible if the starting materials of the formulation can be metered uniformly. The latter is only possible if the applied PVA shows an adequate flowability, and if it is easy to load into the feeder, and shows good homogeneity together with active ingredients etc.

Examples

(52) Even without any further explanations, it is assumed that a person skilled in the art can make use of the above description in its widest scope. The preferred embodiments and examples are therefore to be regarded merely as descriptive but in no way limiting disclosures.

(53) For better understanding and for illustration, examples are given below which are within the scope of protection of the present invention. These examples also serve for the illustration of possible variants.

(54) The complete disclosure of all applications, patents and publications mentioned above and below are incorporated by reference in the present application and shall serve in cases of doubt for clarification.

(55) It goes without saying that, both in the examples given and also in the remainder of the description, the quoted percentage data of the components present in the compositions always add up to a total of 100% and not more. Given temperatures are measured in ° C.

(56) Now, in order to carry out the following experiments a commercially available PVA is cryo-milled into three charges under different milling conditions (definition of method is following) to obtain different particle sizes and particle distributions of PVA powders:

(57) Charge 1: Particle size in the range of <45 μm;

(58) Charge 2: Particle size in the range of 45-1400 μm

(59) Charge 3: Particle size in the range of >1400 μm

(60) The milled PVA powder is physically blended with active ingredients in an amount of 20-60% by weight, with or without additional plasticizers. The mixture of PVA powder is characterized regarding to the flowability, homogeneity and feasibility of feeding into the extruder feeder.

(61) The analysis of the data obtained indicated, that cryo-milled PVA powders with particles having an average particle size of 63 μm and a particle distribution of d.sub.10<17.25 μm, d.sub.50<63.75 μm

(62) and d.sub.90<169.91 μm

(63) are the most suitable PVA powders to be blended with active ingredients and are easy to be fed into the extruder without any blocking of the feeder. Powders of PVA particles in the C group are not suitable as matrix for melt extrusion due to the blocking of the extruder feeder and because of their inhomogeneity together with applied active ingredients. Powders of PVA particles lower than 45 μm are difficult to be loaded into the extruder feeder due to their bad flowability and due to their tendency to aggregate in the feeder.

(64) Methods and Materials

(65) 1. Raw Materials and Manufacturing Method

(66) 1.1 Materials

(67) Background:

(68) At first, the mixture of HME excipients and ingredients should be fed into the feeder of the extruder unhindered.

(69) To achieve the precise feeding rate, the feeder can also be combined with a computer to control the feeding accuracy of the powder. Therefore, the particle size and distribution is a significant parameter to influence the feasibility and accuracy of extruder feeding. As described above, the milled PVA makes the extrusion process feasible. This means, that the particle size and distribution should be clearly defined with a particle size distribution area. Particles larger than this area cannot be fed into the feeder, because the homogeneity of the ingredient/PVA mixture is a problem due to the segregation of API. Additionally, it is very difficult to control the feeding rate of the mixture with large PVA particles. On the other side, particle sizes lower than in this range have an issue with flowability and feeder blocking. Therefore, it is necessary to define suitable particle sizes and size distribution of PVA powders for their application as hot melt extrusion excipients, which have the benefits of good flowability, easy loading, good homogeneity with active ingredients etc.

(70) Raw Material:

(71) Poly vinyl alcohol 4-88, excipient EMPROVE® exp Ph Eur, USP, JPE, Article No. 1.41350, Merck KGaA, Darmstadt, Deutschland

(72) Raw Material PVA 4-88 for Milling:

(73) This PVA types are as coarse—several millimeters in size: too big to load them into the extruder and difficult to formulate a homogenous solid dispersion system with active ingredients together.

(74) 1.2 Manufacturing Method (Milling Method)

(75) Mill Equipment for PVA:

(76) Aeroplex spiral jet mill, type 200 AS Hosokawa Alpine, Augsburg, Germany

(77) Mill Condition:

(78) with liquid nitrogen as cold grinding. The desired particle size is produced empirically in particular by varying the grinding temperature, to control the particle size of PVA. The grinding conditions are varied until the desired particle size is obtained.

(79) 2. Experiments & Characterization Methods

(80) 2.1 Equipment for Analysis Feeder 1 (Brabender® Mini-Compounder KETSE 12/36 D) Instrument for Angle of repose DIN ISO 4324 Stirrer (not always necessary) Glass Funnel Device for closing or opening the output of the funnel (flap) Transparent plastic receptacle (diameter 10 cm) Measuring block (to measure the cone of the powder) Stand with disk Spirit level Different sizes of sieves

(81) 2.2 Define Different Groups of Particle Sizes of PVA 4-88

(82) Group A: PVA 4-88 Particle Size.fwdarw.<45 μm (D.sub.10=6.2 μm/D.sub.50=27.99 μm/D.sub.90=54.76 μm)

(83) Group B: PVA 4-88 Particle Size.fwdarw.45 μm-1400 μm (D.sub.10=17.25 μm/D.sub.50=63.74 μm/D.sub.90=169.91 μm)

(84) Group C: PVA 4-88 Particle Size.fwdarw.>1400 μm

(85) 2.3 Characterization Methods

(86) 2.3.1 Particle Size and Distribution

(87) Particle size determination by laser diffraction with dry dispersion: Mastersizer 2000 with dispersing Scirocco 2000 (Malvern Instruments Ltd. UK.), Provisions at 1, 2 and 3 bar backpressure; Evaluation Fraunhofer; Dispersant RI: 1,000, obscuration limits: 0.1-10.0%, Tray Type: General Purpose, Background Time: 7500 msec Measurement Time: 7500 msec, implementation in accordance with ISO 13320-1 and the details of the technical manual and the specifications of the equipment manufacturer; Information in Vol-%.

(88) 2.3.2. Angle of Repose (DIN ISO 4324)

(89) The Angle of repose gives information about the flowability of the product for example in the feeder (HME), tablet press etc. First of all you have to adjust the disk (with the stand on it). To set up the equipment, proceed as the picture. After that you can fill in your powder into the glass funnel (two-thirds). Attention: Ensure that the flap under the funnel is closed! Now you can start opening the flap and let your powder trickle into the transparent plastic receptacle under the glass funnel. If necessary, use the stirrer! When the powder is on the wraparound edge of the plastic receptacle, close the flap and measure the height of the cone. Repeat it five-times!

(90) Mathematical Formula for Tamped Density:

(91) $\mathrm{Arc}\tan \left(2*\frac{\mathrm{height}}{\mathrm{diameter}}\right)$

(92) 2.3.3 Feeding-Rate into the Extruder

(93) The feeding-rate of excipients powder into the feeder is evaluated with a real feeder of Brabender® Mini-Compounder KETSE 12/36 D)

(94) 2.3.4 Homogeneity with APIs

(95) The present examples are carried out using poorly soluble active ingredients. Indomethacin is used here as a representative model substance. Indomethacin is in water a poorly soluble active ingredient [0,937 mg/L, at 25° C.].

(96) The applied polymer [polyvinyl alcohol (PVA)] with different particle size and distribution is blended with 30% API (indomethacin) powder. Real concentration of indomethacin from different positions of the mixture is detected by NMR spectroscopy.

(97) Determination of Indomethacin Content by NMR Spectroscopy

(98) For determination of the Indomethacin content about 20 mg of sample and 20 mg of maleic acid are exactly weighted and dissolved in DMSO-d6. The clear solution is transferred into a 5 mm NMR tube. The 1H-NMR spectra are recorded on a 500 MHz Bruker Avance III spectrometer equipped with a cryo-cooled TCI probe. The FID is digitized by 128 K data points over a spectral width of 25 ppm. A total of 32 spectra are accumulated with a relaxation delay of 10 s between each scan. Prior to the Fourier transformation, the recorded FID is multiplied with an exponential function (Ib=0.3 Hz). The phase and the baseline is corrected for the obtained spectrum.

(99) For calculation of the Indomethacin content the resonance of the CH protons of maleic acid (ca. 6.3 ppm) and the CH protons of Indomethacin (e.g. 6.7 ppm, 6.9 ppm or 7.0 ppm) are integrated. The integral of maleic acid is set to 100. The content is calculated according to the general formula:

(100) $w_x\left[\%\right]=w_{\mathrm{st}}\left[\%\right].Math.\frac{z_{\mathrm{st}}{M}_x{I}_x{m}_{\mathrm{st}}}{z_x{M}_{\mathrm{st}}{I}_{\mathrm{st}}{m}_x}$ w.sub.St [%]=content of standard in % z.sub.St=number of protons of standard contributing to the signal M.sub.x=molar mass of the compound of interest x I.sub.x=integral of the signal of the compound of interest x m.sub.St=weighted mass of the standard z.sub.x=number of protons of the compound of interest x contributing to the signal M.sub.St=molar mass of the standard I.sub.St=integral of the signal of the standard m.sub.x=weighted mass of the compound of interest x

(101) FIG. 1: shows a NMR spectrogram of 20 mg indomethacin and 20 mg maleic acid in DMSO-d6

(102) 3. Research Results

(103) 3.1 Particle Size and Distribution

(104) Group A:

(105) PVA4-88<45 μm: D.sub.10=6.2 μm/D.sub.50=27.99 μm/D.sub.90=54.76 μm

(106) A milled PVA powder of PVA 4-88 having this particle size distribution is characterized by the logarithmic plot of particle sizes ranging up to 100 microns to their volume percentage. FIG. 2: shows the volume-particle size plot of PVA 4-88, having a particle size distribution of D.sub.10=6.2 μm/D.sub.50=27.99 μm/D.sub.90=54.76 μm

(107) Group B:

(108) PVA4-88 45-1400 μm: D.sub.10=17.25 μm/D.sub.50=63.74 μm/D.sub.90=169.91 μm FIG. 5: shows the volume-particle size plot of PVA 4-88, having particle size distribution of D.sub.10=17.25 μm/D.sub.50=63.74 μm/D.sub.90=169.91 μm

(109) 3.2 Flowability

(110) There are differences in the flowability, if PVA powders as characterized above (Group A, Group B and Group C) are compared with each other and there are additional effects in the flowability if the different PVA powders are mixed with APIs (Active Pharmaceutical Ingredients), so that flowabilities differ between mixtures with and without APIs. FIG. 3: shows the differences in the angles of repose of PVA powders of Groups A, B and C without the addition of any API

(111) 3.3 Results of Feeding-Rate

(112) TABLE-US-00001 with API (30% Difference Particle Load without API Indomethacin) (Without API .fwdarw. size rate (Maximum) (Maximum) With API Group A 170 g/h 1.157 kg/h 1.189 kg/h +0.032 kg/h Group B 170 g/h Not 1.415 kg/h — determined! Group C 170 g/h 3.246 kg/h 1.951 kg/h −1.295 kg/h

(113) Feeding Performance:

(114) In the figures FIG. 4a to FIG. 4c) the feeding rate of the PVA grades of Groups A and B is compared with and without addition of APIs. The comparison shows that the flowability of the powder without any API is also decisive for the flowability and on the uniformity of feeding rate of the blend with API. FIG. 4a: shows the feeding performance of PVA powder of Group A without API. The feeding is not uniform and shows irregularities. FIG. 4b: shows the feeding performance of PVA powder of Group A with 30% by weight of API. The feeding is not uniform and shows comparable irregularities as the feeding of the pure powder. FIG. 4c: shows the feeding performance of PVA powder of Group B without API. The feeding is very uniform. FIG. 4d: shows the feeding performance of PVA powder of Group B with 30% by weight of API. The feeding is also very uniform and is comparable to the feeding of the pure powder of Group B.

(115) No diagram for PVA having mean particle size >1400 μm (Group C) could be performed, because the loading of these particles is not feasible! The feeding rate is not determined, because the particles of the mixture are too large The particles are micronized in the feeder! Loud grating in the feeder and danger that the feeder could be damaged! Measurement had to be interrupted!

(116) 3.4 Homogeneity of Extrusion Mixtures with API

(117) TABLE-US-00002 TABLE 1 Homogeneity of drug distribution in the extruded product Concentration of Compounds indomethacin Average Error Bar PVA4-88 <45 μm 31.10% 31.70% 0.009 (Group A) + 30% 31.80% Indomethacin 31.40% 33.40% 31.20% 31.30% PVA4-88 45-1400 μm 30.90% 30.83% 0.006 (Group B) + 30% 31.00% Indomethacin 30.70% 31.80% 30.60% 30.00% PVA4-88 >1400 μm 16.40% 20.48% 0.042 (Group C) + 30% 25.10% Indomethacin 17.10% 17.60% 20.60% 26.10%

(118) The data of this table show that no homogeneous drug distribution in the extruded product can be obtained if a PVA powder is used having a particle size distribution of >1400 μm (Group C). In this case a separation of PVA particles and of API particles seems to occur before the mixture can be feed into the extruder.

(119) 3.5 Summary

(120) Benefits of the Optimized Particle Size: better flowability in the feeder with and without API more homogenous better results in analysis equal distribution of the API in polymers.fwdarw.amorph suitable particle size distribution and equal particles 4 improved tableting process

(121) The best cryo-milled PVA powders show the following particle size distribution:

(122) TABLE-US-00003 D10 D50 D90 (μm) (μm) (μm) Cryo-milled PVA 17.25 63.74 169.91 FIG. 5: shows the volume-particle size plot of PVA 4-88, having the advantageous particle size distribution of D.sub.10=17.25 μm/D.sub.50=63.74 μm/D.sub.90=169.91 μm.

(123) Advantageous Properties of PVA Powders Having an Optimized Particle Size Distribution as Characterized Above:

(124) The experiments show the relationship of the particle size distribution of PVA in relation to the flow properties as well as in relation to its suitability for its dosage into the feeder of an extrusion plant for hot melt extrusion.

(125) By the experiments carried out it was found, that PVA powders having suitable particle sizes and size distributions can be used very well for hot melt extrusion excipients thanks to improved flow properties, their easy-to-load and good homogeneity with APIs and so on.

(126) But PVA powders having particles larger than in this defined range cannot be continuously loaded into the feeder without any undesirable clumping and blocking of material supply in the feeder and the homogeneity of the API/PVA mixture is a problem due to the segregation of the comprised API. On the other hand, also particle size distributions, which are lower than the optimal size distributions found here, lead to issues with the flowability and to a blocking of the feeder.

(127) In addition, PVA powders according to the present invention, which have in aqueous solution a viscosity* ≤40 mPa.Math.s, show the advantage to be (hot) melt extrudable by themselves without the addition of any processing aids like additional plasticizer or other active ingredients (* viscosity is measured as 4.0% water solution at 20° C. DIN 53015).

(128) However, PVA powders, which have in aqueous solution a viscosity* ≥40 mPa.Math.s, need additional plasticizer or active ingredients as plasticizer to make the mixture extrudable.