Pulverulent mannitol and process for preparing it

Details Pulverulent mannitol and process for preparing it Pulverulent mannitol and process for preparing it

2001-03-28

2004-06-01

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

Reexamination Certificate

active

06743447

ABSTRACT:

The aim of the present invention is a pulverulent mannitol with a fine particle size, high density and excellent flow capability, and also having a high mannitol content and rapid rate of dissolution In water.
The invention also concerns a process for manufacturing the said mannitol as well as its use in the fields of pharmaceuticals and foodstuffs.
The pharmaceutical and foodstuffs industries consume large amounts of pulverulent polyols as excipients, bulk sweeteners or as carriers for additives. More precisely this involves sorbitol, xylitol, mannitol and maltitol.
Sorbitol has the advantage of being the least expensive product among these three polyols, which explains the fact that it is used very often. Nevertheless, as soon as any re-uptake of water has occurred, its high hygroscopicity leads to a product whose flow is difficult or even impossible.
To avoid this problem, a sorbitol with a coarser particle size is chosen, but then the time taken to dissolve in water generally becomes excessively long. In addition, the highly hygroscopic nature of sorbitol renders any use of this polyol out of the question when it is associated with active principles or ingredients that are very sensitive to water.
With regard to xylitol, this is scarcely ever used as an excipient because it has the disadvantage of caking under conditions of normal humidity, and does so even more readily than sorbitol.
Because of its low hygroscopicity, mannitol could be an excellent excipient since it is compatible with the majority of active ingredients, but unfortunately the product obtained by crystallisation in water beginning with a supersaturated solution has mediocre flow properties.
In fact, crystalline mannitol is excessively friable, leading to the formation of fine particles that are particularly detrimental to its flow properties.
In addition, because of its compact crystal structure, mannitol obtained by crystallisation in water has a poor ability to dissolve. This slow dissolution rate, although it can be an advantage in certain special applications, is always considered to be a major disadvantage in the cases that are of interest here, which hinders its use.
Other pulverulent forms of mannitol together with the means for obtaining the latter are described in the literature.
For example U.S. Pat. No. 3,341,415 deals with a method for preparing a pharmaceutical excipient containing at least 20% by weight of mannitol and an additional sugar chosen from among lactose, saccharose, erythritol, galactose and sorbitol. However, the process described is very tricky to operate on an industrial scale. Moreover, the product obtained is highly hygroscopic, very compact and very difficult to dissolve in water.
The patent application JP 61.85330 relates to a process for preparing excipients characterized by the fact that it consists of drying D-mannitol by spray atomization. However, it appears that the products obtained in this way contain more than 50% of particles smaller than 75 &mgr;m, which is detrimental to the correct flow of the product.
U.S. Pat. No. 3,145,146 describes a process for modifying the physical properties of mannitol by spray-drying, and the product thus obtained.
A powder whose particle size lies between 5 and 100 &mgr;m is obtained. However, this process consists of adding a binder, which can be a paraffin, a gum or a cellulose derivative, before the spray-atomization stage. In addition, at least 50% of the powder particles still have a size smaller than 75 &mgr;m, which is far from being ideal to obtain good flow.
All of the above shows that there is an unsatisfied need to have available a mannitol for use as an excipient that has a fine particle size, a high density and an excellent flow ability, it being advantageous for these properties to be combined with a high mannitol content and a rapid rate of dissolution in water.
Furthermore, in order for this excipient to be preferred for use as a powder to fill hard capsules, it has been found that it is necessary to have a product that will be compatible with the active ingredient with which it is associated, and that its free-flowing properties, homogeneity of mixing, dissolution profile and packed density conform to the required application.
To obtain an excipient of this kind having all the functional properties listed above, the applicant company has discovered that, contrary to all expectation, it is advisable to choose from among the polyols a pure crystalline mannitol and to modify its physical properties by using a suitable process such that it has at the same time a fine particle size, a high density and excellent flow capability, and in addition a high mannitol content and a rapid speed of dissolution in water.
Thus the applicant company has distinguished itself by reconciling all of these aims that were up to this time supposed to be irreconcilable, by devising and developing, through numerous investigations, a novel pulverulent mannitol.
Thus the invention relates to a pulverulent mannitol characterized in that it has:
an average diameter of between 60 and 200 &mgr;m, preferably being between 80 and 180 &mgr;m,
a packed density, determined according to a Test A, of between 0.65 and 0.85 g/ml, preferably between 0.7 and 0.8 g/ml,
a flow factor of at least 60, preferably between 60 and 90.
The pulverulent mannitol according to the invention has an average diameter of between 60 and 200 &mgr;m, preferably between 80 and 180 &mgr;m. These values are determined on a COULTER® LASER LS granulometer by determining the volume size distribution of the particles of pulverulent mannitol.
Thus the size of the component particles of the pulverulent mannitol according to the invention enables it to maintain an average diameter relative to that of the majority of active ingredients and thus to obtain homogeneous mixtures of active ingredients with mannitol by granulometric (particle size) equivalence.
In fact, it has been found quite generally that an elevated active ingredient crystal size impairs their dissolution speed. Therefore an average diameter of between 80 and 200 &mgr;m is recommended.
The pulverulent mannitol according to the invention can also be characterized by its packed density.
The determination of the packed density is carried out according to the method specified in the operating instructions for the HOSOKAWA P.T.N. powder tester.
Under these conditions, the pulverulent mannitol according to the invention has a high packed density, i.e. comprised between 0.65 and 0.85 g/ml, and preferably comprised between 0.7 and 0.8 g/ml.
This high density value gives the pulverulent mannitol according to the invention properties that are particularly appropriate to its use as a filling agent for small hard capsules in pharmacology, namely a size that is more acceptable by patients.
In addition, the pulverulent mannitol according to the invention can also be characterized by its flowability, this property being especially appropriate when the said mannitol is used to fill hard capsules.
The ability of the said mannitol to flow is measured using the POWDER TESTER instrument marketed by the HOSOKAWA Company. This equipment enables the ability of a powder to flow to be measured under standardised, reproducible conditions and the calculation of a flow factor, also called the Carr Index.
The pulverulent mannitol according to the invention has an excellent flow factor, generally at least 60 and preferably of between 60 and 90.
This value is generally much better than that of the crystalline mannitol powders of the prior art, and is equivalent to mannitol powders obtained by extrusion or atomisation processes.
However, the products obtained by extrusion usually have a large particle size with an average diameter of between 250 and 600 &mgr;m, and those obtained by atomisation typically have a low packed density, less than 0.6 g/ml, which makes these two categories of product particularly poorly suited to the required areas of application.
The pulverulent mannitol according to the invention is characterised in that it also has a mannitol co

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