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US-12616660-B2 - Compressible and free-flow co-agglomerates of crystalline mannitol and granular starch

US12616660B2US 12616660 B2US12616660 B2US 12616660B2US-12616660-B2

Abstract

Coagglomerates of crystalline mannitol and granular starch have a laser mean volume diameter D4,3 of between 60 and 500 μm, a ratio of mannitol/starch is between 99.5/0.5 and 50/50, and the mannitol is both in the alpha and beta crystalline forms.

Inventors

  • Baptiste Boit
  • Alain Francois
  • Philippe Lefevre
  • Damien Passe

Assignees

  • ROQUETTE FRERES

Dates

Publication Date
20260505
Application Date
20210924
Priority Date
20090430

Claims (9)

  1. 1 . Coagglomerates consisting essentially of crystalline mannitol and granular starch, wherein the coagglomerates have: a laser mean volume diameter D4,3 of between 100 and 250 μm, a ratio of mannitol/starch is between 99.5/0.5 and 50/50, and the mannitol is a mixture consisting of both alpha and beta crystalline forms, wherein the crystalline mannitol has a laser mean volume diameter of approximately 50 μm, and the coagglomerates have a tableting capacity from 200 N to 450 N and a flow grade between 3 and 15 seconds.
  2. 2 . The coagglomerate as claimed in claim 1 , wherein the mannitol/starch ratio is between 95/5 and 70/30.
  3. 3 . The coagglomerate as claimed in claim 1 , wherein: an aerated density is between 0.400 and 0.750 g/ml, and a tapped density is between 0.500 and 0.850 g/ml.
  4. 4 . The coagglomerate as claimed in claim 1 , wherein: an aerated density is between 0.450 and 0.650 g/ml, and a tapped density is between 0.550 and 0.750 g/ml.
  5. 5 . The coagglomerate as claimed in claim 1 , wherein the starch is selected from the group consisting of standard corn starch, extra white corn starch, and potato starch, taken alone or in combination.
  6. 6 . The coagglomerate as claimed in claim 1 , wherein the coagglomerate consists of said crystalline mannitol and said granular starch.
  7. 7 . The coagglomerate as claimed in claim 1 , wherein said granular starch is a native or modified starch having retained its granular structure.
  8. 8 . The coagglomerate as claimed in claim 3 , wherein the aerated density is between 0.450 and 0.650 g/ml.
  9. 9 . The coagglomerate as claimed in claim 3 , wherein the tapped density is between 0.550 and 0.750 g/ml.

Description

A subject matter of the present invention is coagglomerates of crystalline mannitol and of granular starch which exhibit an outstandingly high tableting capacity, which marks them out very particularly for the preparation of tablets. The invention also relates to coagglomerates of crystalline mannitol and of granular starch exhibiting an excellent ability to flow, which also marks them out for use in the filling of hard gelatin capsules. Finally, the invention relates to the process which makes it possible to obtain these coagglomerates. In the field of the use of polyols, as regards the field with which the present invention is specifically concerned, namely pharmaceutical excipients and bulk sweeteners used in the food industry, several pulverulent polyols are commonly used. They are sorbitol, xylitol and especially mannitol. The pharmaceutical industry consumes large tonnages of mannitol. The latter is used in particular as excipient in the dry forms, which are, for example, powders for filling hard gelatin capsules, powders for a sachet to be dispersed or dissolved at the time of use in water, solid oral forms and tablets. This is because mannitol, due to its flavor and the very low hygroscopicity of its crystalline form, constitutes an excellent excipient, in particular for its very high chemical inertia with regard to the active principles. Unfortunately, the product obtained by crystallization in the water from a supersaturated solution is not naturally compressible. In order to remedy this situation, it is known by experts in the field to add a binder in order to increase its tableting capacity. U.S. Pat. No. 3,145,146 describes, for example, a process consisting in using paraffin wax, gum or a cellulose derivative as binder before the step of spray-drying resulting in the preparation of the mannitol powder. However, this technical solution is not prized by the user. It is known by a person skilled in the art, for the preparation of hard gelatin capsules, that the mixtures capable of being used for the filling of hard gelatin capsules have to be able to lend themselves to automatic filling, in order to guarantee a uniform dosage. It is obvious that a pharmaceutical dosage formulation operation is necessary for some substances, in order to ensure uniform and exact filling on very high speed machines. Care should in particular be taken with regard to the following parameters: shape and size of the particles,uniform particle size,homogeneity of the mixture,flow property of the powder,moisture level,good agglomeration under pressure. In point of fact, next to its non tableting capacity, it is necessary to add another disadvantage of the mannitol obtained by crystallization in water, which is that it exhibits mediocre flow properties due to the orthorhombic structure of its crystals and in particular due to its excessive friability. This friability results in the formation of fine particles which interfere in particular with its flow properties, especially during the filling and the emptying of the hoppers and chutes for feeding the devices employed to manufacture tablets or to fill hard gelatin capsules. For this reason, the mannitol crystallized in water is certainly not an excipient of choice which can be used in the filling of hard gelatin capsules. Here again, it is necessary to add a binder. In the U.S. Pat. No. 3,145,146, the addition of binder does not, however, prevent at least 50% of the particles of the powder from still having a size of less than 75 μm, which is far from being ideal in producing good flow. In the field of tablets, starch can advantageously be used as binder when it is subjected to a precooking and can also act as diluent. Furthermore, it has good disintegrating properties due to its hydrophilicity in water when it is employed in the granule form. However, it has to be incorporated in a high amount, generally of greater than 15% of the final formulation. On the other hand, it exhibits, due to the small size of its particles and its low density, the disadvantage of not flowing. The high elasticity of its granules furthermore confers a very poor tableting capacity on it, which does not make possible the manufacture of tablets of satisfactory hardness. A person skilled in the art thus cannot envisage combining mannitol and granular starch in order to take advantage of the binding properties of the starch for providing the mannitol with the tableting capacity or flow properties which are lacking in it. In fact, if the combination of starch and mannitol was practiced, it is rather in the field of the manufacture of orodispersible tablets, where it has been in particular a matter of taking advantage of the disintegrating and diluting properties of the starch. For example, a description is given, in patent application WO 00/47233, of a preparation for tablets comprising the physical mixture of an active ingredient and a starch with in particular mannitol. In point of fact, it is stro