WO2000062916A1

WO2000062916A1 - Continuous pelletizer and spheronizer

Info

Publication number: WO2000062916A1
Application number: PCT/PT2000/000002
Authority: WO
Inventors: João Fernandes de Abreu PINTO; Cristina N. Abreu
Original assignee: Pinto Joao Fernandes De Abreu; Abreu Cristina N
Priority date: 1999-04-19
Filing date: 2000-04-18
Publication date: 2000-10-26
Also published as: AU4153400A; PT102287A; EP1119406A1

Abstract

The invention relates to an equipment that can be used to prepare agglomerates of particles in the solid state at room temperature. The agglomerates produced are highly spherical and dense. The agglomerates can be used to carry an active ingredient for medical, pharmaceutical, nutraceutical, chemical, agricultural or other related activity that can be released immediately or in a controlled fashion. The equipment incorporates several parts namely several concentric chambers (Re, Rm, Ri (1)) to a vertical axis closed at the top by a lid (2) and at the bottom by a rotating plate (3). The surface of the plate may be smooth or engraved with a defined geometric pattern. The plate rotates at different speeds due to its connection to a motor (4). The processing material is feed in the internal chamber, processed and moved to the next chamber. The movement of the material carries on in a cascade like movement until it reaches the last chamber being discharged from the equipment (5).

Description

CONTINUOUS PELLETIZER AND SPHERONIZER

The present invention relates to an equipment designed to prepare pellets, i.e., agglomerates of particles in the solid state, at room temperature with a closely spherical shape, which in the presence of a liquid, may disintegrate, or simply release an active ingredient. Pelletisation is a process of agglomeration that transforms fine powders into small, free-flowing spheroids. The active ingredient is generally released in a controlled manner, preferably over an extended period of time, into the liquid environment. The active ingredient may be a pharmaceutically active ingredient, a compound for water treatment, a pesticide or herbicide, or nutrient. Pellets are of particular interest as orally administered controlled release pharmaceuticals or as intermediates in the production of other products (e.g. medicines).

Granulation, or pelletisation, can be achieved by various techniques, as described by Ghebre-Sellassie [Pharmaceutical Pelletisation Technology, 1989]. The type of equipment related to the one described in the present invention, is the one that produces pellets by extrusion and spheronisation. In this system, the spheroniser, also known as marumerizer, incorporates a vertical cylindrical chamber containing a rotating plate at the base, a lid at the top and a port for discharge of the pellets on the side. Both the speed of rotation and the surface of the rotating plate can be changed according to the user's needs. This plate's surface can be flat and smooth, rough, or engraved with a defined geometric pattern (cross- hatch or radial-hatch design), therefore increasing the attrition and friction between the plate and the material being processed.

Various applications of an equipment like the one described can be found in the literature, for instance, in the production of pellets by a technology known as extrusion and spheronisation. The addition of paniculate matter to the device in the presence of a liquid, solution or suspension contributes to the agglomeration of the powders a process known as rotogranulation. Other possible field of application is in the preparation of spheroids from rods produced by extrusion of materials. These extrudates can be produced from masses, preferably wet masses, and preferably containing mixtures of an active ingredient and microcrystalline cellulose. These extrudates are submitted to a rotational movement (toroidal) where they are shaped into spheroids. Briefly, the spheronisation modifies the size and shape of extrudates namely the ones produced in an extruder fitted with a cylindrical, single or multiple die. The extrudates produced are transferred to the spheroniser where they are chopped into small rods. This shaping process requires the masse to be plastic in nature. The physical properties of these rods are modified both in their shape (become spherical) and mechanical structure (the mechanical strength and the density increase). In order to produce pellets from raw materials in the powder state it is possible to add powders to a pan and at the same time spraying an agglutination liquid phase. The air may also be used to dry the forming pellets. Compared to other pelletizing methods, extrusion and spheronisation is claimed to produce pellets with high sphericity, density, mechanical strength and release the active ingredient in a more controllable fashion. Moreover, a sphere shows several geometric advantages over other forms. For instance, it has the lowest surface-to-volume ratio and because of this shape, an uniform coat is easier to achieve.

The first patent known regarding the technology of spheronisation has been granted to Nakahara in 1966 and the original process has been modified continuously since then. All the equipments commercially available work in a discontinuous fashion. A typical processing cycle consists of loading the chamber with a predefined amount of material, allowing it to be processed for a period of time until a certain degree of sphreronisation or shape is accomplished, discharge the spheroniser and restart a new cycle. With such a design the spheronisation is a discontinuous process. Manufacturers supply spheronisers with two units (chambers) that work alternatively, i.e., when one is processing the extrudates, the second one is being loaded with new extrudates coming from the extruder. An equipment such the one described presents several disadvantages: First it assumes that the spheronisation is a discontinuous process, that implies a variability between batches. Secondly, the manufacture of such an equipment is more troublesome, thus, more expensive and more difficult to maintain. Thirdly, the size of the equipment is large. Fourth, the automation of such spheroniser implies the automation of both units. According to the invention it is proposed a new device to prepare pellets from powders, preferentially from agglomerated powders produced by extrusion. The basic components of such device are as follows: one plate of variable diameter (ranging from 10 cm up to 50 cm or more), rotating at a variable speed (ranging from 20 rpm up to 2000 rpm) with a smooth surface or a rough surface engraved in a defined pattern (e.g. cross-hatch or radial-hatch design); one or more concentric walls, forming independent chambers, preferably 3 chambers with 23, 19 and 15.2 cm in diameter and 13.9 cm height; each chamber has a port allowing the passage of the processing materials from one chamber to the next due to the centrifugal force applied continuously to the materials. Each port can be open/closed by a mechanical, pneumatic or other adequate system; one lid to confine the chamber for protection of the material and as a port for loading the internal chamber. The constructing material for the plate and chambers can be stainless steel, whereas the lid can be made of an acrylic polymer, in order to be possible to visualise the inside of the chambers (Figure 1 presents a schematic representation of the device of the invention).

The invention thus takes advantage of the radial/centrifugal force applied to the materials and the large diameter of the common plates to produce several batches of pellets at the same time. In the most internal chamber the material is loaded suffering the first shaping and, after a predefined period of time is allowed to move to the second chamber to improve the shaping of the particles. Immediately after, the first chamber can be loaded with fresh material. The material in the second chamber can move to next one, and the process goes on until the pellets reach the last chamber where they are discharged from the equipment. The overall movement can be regarded as a cascade in which the spheroids move from the inner chamber to the outer chamber and finally out of the spheroniser.

The invention is of most benefit for solid dosage forms, i.e. where the active ingredient is a pharmaceutical active ingredient. However, the invention may be also of value for the compounding of active ingredients for water treatment, pesticides or herbicides or nutrients, presented to plants, animals or humans as solid state products.

The pellets may contain excipients which contribute to the desired physical properties, particularly chrushability, density and sphericity of the pellet. The excipients are selected according to their suitability for the intended use of the pellets, so that for a pellet to be used as a pharmaceutical dosage form, the excipient should be pharmaceutically acceptable. The excipient may comprise a mixture of components to provide the desired properties. For instance it may comprise a polymeric binder material. Suitable binders are, for instance, cellulose-based binders, especially microcrystalline cellulose. Furthermore, the excipient may comprise a diluent, such as a sugar, especially lactose.

The pellets are generally provided with controlled release properties, such that they release the active ingredient over an extended period of time when dispersed in a liquid. The controlled release binder may comprise a matrix binder, which is dispersed throughout the body of the pellet. The invention is of particular value where the controlled release binder consists of a surface coating on the pellets. The coating generally comprises a film-forming binder, usually comprising a polymer binder, for instance a synthetic or naturally derived polymer binder, such as an enteric coating. Commercially available binders for enteric coating such as cellulose ether or esters derivatives, e.g. cellulose acetophthalate or acrylic resins, or gums or sugars may be used. It is believed that the coating around a pellet will remain relatively undamaged. In order to minimise damage it may be desirable to incorporate a plasticiser into any coating formulation of the active pellets. The plasticiser may be an internal (built in to the binder polymer) plasticiser or an external plasticiser, that is a separately added component to the coating mixture. Consequently, pellets highly uniform in size, shape and surface will be coated in a better way.

Alternatively the pellets may comprise a disintegrating component which allows the pellet to disintegrate upon contact with a body of liquid, usually an aqueous liquid, for instance gastric juices in the stomach of a patient to whom the pellet has been administered. Suitable disintegrable components are selected so as to provide the change in physical properties, that is cohesion of the components in the pellet, upon addition to a liquid, usually an aqueous solution. The disintegrating components may be readily soluble in the liquid. On the other hand, the disintegrating component may swell upon contact to a liquid, leading to the fracture of the pellet. However, most swellable organic pharmaceutically acceptable compounds can lead to an increased cohesion between pellets. Preferably, the component may be one with low adhesive and cohesive properties. These characteristics contribute to the disintegration of the pellets upon contact to the liquid. Suitable disintegrating agents which have low adhesive and cohesive properties are generally water insoluble inorganic salts such as barium sulphate, calcium carbonate, calcium phosphate, magnesium silicate and dicalcium hydrogen phosphate. These disintegrating pellets generally comprise a binder, selected so that the pellets have the desired mechanical properties to allow them to be included into capsules or tablets and allow the disintegrating component to have its desired effect upon addition of the capsule or tablet to a liquid. The binder is suitably a cellulose binder, for instance microcrystalline cellulose.

By formulating these materials in the extruder it is possible to produce in a continuous fashion the materials and producing pellets with different properties. The pellets produced in each production cycle present the same size, mechanical strength, density and sphericity. The higher outputs led to a higher production of pellets that can be used as such or are part of gelatine capsules or tablets. The pellets may present several sizes, densities or mechanical strength but, pellets within the range 0.71-1 JO mm in diameter, 1.40 up to 1.60 gem^"3 in density and a force required to crush the pellets higher than 15N is desirable.

To produce pellets with such characteristics a modified marumeriser or spheroniser with different chambers, particularly 3, can be used. Stainless steel is the preferable material to make such equipment, although other materials should not be excluded. The rotating plate, with a smooth surface or, preferably with a engraved surface rotates at different speeds, particularly 1000 rpm. The chambers can be closed with a lid made of a transparent material such as an acrylic polymer. Each chamber may have a port for discharge or be lift to release the contents to the next chamber. The movement of the forming pellets carries on in a cascade type.

Pellets were produced from extrudates with different shapes especially cylindrical in shape and 1 mm diameter. The extrudates have shown a smooth surface and no other defects were observed, stressing the homogeneous nature of the extrudate. Pellets containing an active ingredient, or not, having a mean diameter in the range 0.5-5 mm, comprising the active ingredient and an excipient, which have a crushability of at least 5N, a density of at least 1.3 gem^"3 were produced separately in each chamber or continuously in all chambers. Pellets were used to fill a shell, made preferably from gelatine or, to be used in tabletting either coated or uncoated with a polymeric material particularly from cellulose or cellulose derivatives, acrylic acid or derivatives or others in order to modify the release of the active ingredient in an aqueous medium or, simply to protect the active ingredient from an undesirable environment such as light or acidic or basic environment that will degradate the active ingredient or simply modify its stability throughout time.

The crushability is determined using an apparatus containing two horizontal parallel plates that apply a force to crush the pellet. An equipment such as the CT40 Engineering Systems apparatus, used as standard pharmaceutical crushability test can be used to perform such test. The device supplies a force over the pellet when the upper part moves down at a constant rate. The force increases until the pellet is crushed. The value of the maximum force applied is recorded. The crushability of a batch of pellets is the mean of a number of tests on similar pellets.

The density of the pellets produced by the equipment described by the invention can be measured by a pycnometer. A pycnometer is a device described in the literature used to measure the relationship between the mass and the volume occupied by a sample material. In practice the measurement of the density of the materials provides information about their structure, thus allowing the comparison between pellets produced by different equipments or from different raw materials.

High sphericity is a desirable characteristic that should be pursued for pellets because further processing can take advantage of the spherical shape of the pellets such as coating with a binder polymer to protect or modify the release of the active ingredient. Several techniques can be used to assess the sphericity of the materials. The measurement of two dimensions of the pellet on orthogonal axis, one being the largest dimension possible, can be done over a sample of pellets by microscopy. The ratio between the largest dimension over the orthogonal provides a measure to assess the sphericity of a particle. Obviously, for a sphere the ratio is unity.

The invention is further illustrated in the following examples:

Example 1: Preparation of pellets in the extruder

Mixtures of cellulose microcrystalline, lactose and water (5:5:5.5 on a dry weight basis) were mixed (Kenwood Chef, mixer), firstly the microcrystalline cellulose with lactose and then the water was added (Table 1). The total time for the mixture was 15 minutes. The wet masse formed was allowed to stand for 15 hours in a sealed plastic bag to ensure good water distribution before further use. This step, although convenient could have been avoided with minor modifications of the formulation. The wet mass was then extruded in a ram extruder mounted in a mechanical press (Lloyd instruments, MX50) fitted with a 50kN load cell. The crosshead was displaced at 200 mm/min and the mass was extruded through a die with 1 mm diameter with a length/diameter ratio of 8.

7αb/e 1

Example 2: Assemblage of the spheroniser

Different cylinders with the diameters of 23, 19 and 15.2 cm and a height of 13.9 cm and a thickness of 0.3 mm made of stainless steel were assembled together in a fixed concentric way each one presenting one port for discharge of the material from the chamber. Below the cylinders a rotating plate connected to a motor was rotating at 1000 rpm. On top of the chambers a lid was placed. Thus, the assemblage formed 3 independent chambers. The extrudates were placed in the inner, medium and outer chambers and spheronised at different times. At different experiments extrudates were placed in the inner chamber and then allowed to move to the medium chamber and then to the outer chamber, in a cascade like movement. For reference it was used a commercially available spheroniser to compare the results with the one proposed in this invention.

Example 3.1 : Preparation of pellets in a commercial spheroniser

Extrudates produced according to example 1 were spheronised in a commercial spheroniser, single chamber with 23 cm diameter - Ro - and 13.9 cm height at different times. The plate was rotating at 1000 rpm and the surface was radially engraved. Examples of processing times for the commercial spheroniser are presented in Table 2. Table 2

Example 3.2: Preparation of pellets in the new spheroniser

Extrudates produced according to example 1 were spheronised in the new spheroniser with different diameter chambers. R_e, R_m, R„ the external or outer chamber, the medium chamber and the inner chamber, respectively and 13.9 cm height at different times. The plate was rotating at 1000 rpm and the surface was radially engraved.

Table 3

Example 3: Characterisation of the pellets

The spheres produced in examples 3JJ to 3J.5 and 3.2J to 3.2J5 were analysed for their weight loss throughout the spheronisation process (weight loss after drying overnight at 105°C), for their particle size and size distribution (by sieve analysis), crushing force, density (by Micromeritics helium pycnometer), crushing force (by crushing the pellets between two plates). The results are shown in Table 4.

7αb/e 4

Examples 3JJ to 3.1.5, 3.2J to 3.2.5, 3.2.6 to 3.2J0 and 3.2J 1 to 3.2J5 show that for any chamber considered the moisture content of the pellets decreased continuously with spheronisation indicating that drying of the wet extrudate occurred throughout the process at almost the same rate for the different chambers considered.

Regarding the particle sizes of the different examples, no significant difference was observed between the pellets produced in the different chambers for the same time of spheronisation. The observation is also supported by the values of the interquartile range that are not significantly different, particularly between the examples 3 J.2 to 3.1.5 and 3.2.2 to 3.2.5. The results for the density have shown that the pellets produced by any of the equipments considered are identical independently of the chamber considered. The mechanical strength of the pellets assessed by the crushing force required to break the pellets followed the same pattern for any of the pellets considered at any time of spheronisation. The shape of the pellets produced did not change with the chamber considered but exclusively with the time of spheronisation. The general pattern was an evolution towards the unity, i.e., towards a perfect sphere, as the examples 3J.5, 3.2.5, 3.2JO and 3.2J5 suggest.

Claims

1. An equipment to produce spherical particles containing, or not, an active ingredient having several concentric chambers (number may vary between 2 and 15) with a vertical axis.

2. An equipment to produce spherical particles, as described by claim 1, possessing several chambers with smooth surfaces.

3. An equipment to produce spherical particles, as described by claims 1 and 2, built with a horizontal and turning plate that constitutes the bottom of the different chambers.

4. An equipment to produce spherical particles, as described by claims 1 to 3, where the horizontal plate is attached to the axis of a motor that promotes the rotation of the plate with variable speeds (quantified either in terms of the number of rotations per unit of time or by its peripheral linear speed).

5. An equipment to produce spherical particles, as described by claims 1 to 4, which rotating plate shows a smooth or/and a graved surface.

6. An equipment to produce spherical particles, as described by claims 1 to 5, that can be made preferentially in stainless steel.

7. An equipment to produce spherical particles, as described by claims 1 to 6, where its chambers are exposed to the environment or closed completely or partially with a cover.

8. An equipment to produce spherical particles, as described by claims 1 to 7, that allows the simultaneous processing of materials either as individual particles or as agglomerates of particles that are going to be rounded until they reached a spherical shape in a multiphase process.

9. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to process mixtures of materials including a binding agent and a diluent.

10. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to process a pharmaceutical, a nutraceutical, a chemical, an agricultural, or other products with different applications.

11. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used at temperatures ranging from 0 to 60°C.

12. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to produce spheroids with a size ranging from 250 to 2800 μm, preferably 1000 to 1400 μm.

13. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to produce spheroids with densities ranging from 0.90 to 2.50 gcm^"\ preferably 1.40 to 1.55 gem^"3.

14. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to produce spheroids with a mechanical strength (measured by the application of a load over their equatorial plane until the spheroids crush) in the range of 6 to 24N, preferably 15 a 18N.

15. An equipment to produce spherical particles, as described by claims 1 to 7, that can be used to produce spheroids presenting an aspect ratio within the range 1.0-1.5, preferably 1.0-1. L