WO2002092708A1

WO2002092708A1 - Method for preparing an aqueous coating dispersion of starch and an aqueous coating dispersion of starch prepared by that method

Info

Publication number: WO2002092708A1
Application number: PCT/FI2002/000414
Authority: WO
Inventors: Karin Krogars; Jyrki T. HEINÄMÄKI; Jouko K. Yliruusi; Päivi MYLLÄRINEN; Pirkko Forssell; Riitta Lahtinen
Original assignee: Licentia Oy
Priority date: 2001-05-15
Filing date: 2002-05-15
Publication date: 2002-11-21
Also published as: FI20011017A0; FI20011017A

Abstract

The present invention relates a method for preparing an aqueous coating dispersion of starch having good film-forming properties and usability in the room temperature. Further, the present invention relates to a method of coating substrates such as pharmaceuticals, food, agricultural seeds and the like. The films prepared using the aqueous coating dispersion of starch according to the invention have a low oxygen transmission and satisfactory mechanical strength properties as well as good stability during storage.

Description

Method for preparing an aqueous coating dispersion of starch and an aqueous coating dispersion of starch prepared by that method

The present invention relates to a method for preparing an aqueous coating dispersion of starch and to an aqueous coating dispersion of starch prepared by that method. Further, the present invention relates to a method of coating substrates such as pharmaceuticals, food, agricultural seeds and the like.

In pharmaceutical industry native and modified starches have been traditionally used as diluent, glidant, disintegrant, filler and binder applications in the manufacture of tablets and capsules. As a film forming agent for coating applications of pharmaceutical substrates, food, agricultural seeds, and the like, native starches have not been widely used. In food industry different type of starches are used as thickeners and stabilizers.

Film-coating of pharmaceuticals is a common manufacturing stage for the following reasons: (i) to provide physical and chemical protection for the drug, (ii) to mask the taste, odour or colour of the drag or (iii) to control the release rate or site of the drug from the tablet. When a coating composition is applied to a batch of tablets or granules (or to a batch of liquid drops or even gas bubbles), the core surfaces become covered with a polymeric film that is formed as the surfaces dries. The major component in a coating formulation is a film forming agent, which ideally is a high mo- lecular-weight polymer that is soluble or dispersible in the proper solvent (today, most preferably in aqueous-based media). The polymer forms a gel and produces an elastic, cohesive and adhesive film coating.

In pharmaceutical industry, organic-solvent based film coatings have been used for over 40 years. In 1990's, however, interest in the use of aqueous-based film coating systems has been rapidly increasing owing to the well-documented drawbacks (unsafe, toxic, polluting and uneconomic) associated with organic-solvent-based coating systems. Consequently, and for the reasons mentioned above, very much efforts has been focused on the research and development work of new aqueous-based film coating formulations. Up to date, aqueous-soluble/dispersible polymers available on the market consist primarily of either cellulosic polymers or acrylate copolymers, such as hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and methacrylic acid polymers and copolymers. An example of an aqueous dispersion for conventional film coating of tablets is Opadry® (HPMC). There are, however, some material re- lated limitations in using these polymers in aqueous-based film coating such as logo-bridging, cracking and edge splitting.

For characterisation of film forming capacity of new polymers and film properties, the evaluation of free films has proven a useful technique. Free films can be pre- pared by using either casting or spraying technique. The latter one is generally considered to be more realistic representation of the film in its end-use state. Film coating quality and properties, however, should be finally tested with film-coated drug products manufactured by perforated side-vented pan or air-suspension coating methods.

Starch is a cheap, renewable and a biodegradable material that is used as a film forming material in paper and textile industry (Wolff et al. 1951; Langlois and Wagoner 1967). Starch is the reserve polysaccharide of storage organs as seeds, tubers and roots. Production of starches is about 6,5 million tons per year in Europe and the most important sources are corn, wheat and potatoes. Starch occurs in na- ture as partially crystalline granules, and the shape is characteristic of the botanical origin with a size range of 1 to 100 μm. Most of starches are a mixture of two glucose polymers, linear amylose (10⁵ - 10⁶g/mol) and very highly branched amy- lopectin. In normal starches the amylopectin is the main polymer. Corn, barley and rice have varieties, which are composed only of amylopectin. Crops containing pure amylose are not available. In high-amylose corn starch the amylose content is the highest, 70%.

One of the reasons for the lack of using starches as a film forming agent for pharmaceuticals, and the like, is probably that they have to be first cooked (gelatinized) in order to produce a paste, and that the plasticization of the polymer is complex. Gelatinization is a process when starch granules swell irreversible in water while heating and stirring. The increase in the viscosity of the solution depends on the starch origin. Starch granules are insoluble in water at room temperature (20-25 °C).

Film formation properties of starches have been investigated (Langlois and Wagoner 1967; Muetgeert and Hiemstra 1958; Kudera 1961). According to these stud- ies, films seem to be mechanically rather strong and as a consequence of their hy- drophilicity good oxygen barriers. Recently high-amylose corn starch has been suggested to be used as a film former for pharmaceutical applications (Palviainen et al. 2000). This coating process, however, can be performed only under low starch concentration and the solution has to be maintained at above 60°C. It has also been shown that film preparation process has a great influence on amylose film structure (Unbehend and Sarko 1974).

Starches could be used in masking, barrier coating and controlled release applications due to their film formation properties and ability to prevent oxygen transport. Milojevic et al. (1996) mixed extracted amylose with ethyl cellulose and pellets were coated with the dispersions in a fluid bed coater. By using a mixture of amylose and ethyl cellulose in the ratio 1:4 w/w film-coated pellets which exhibited controlled drug delivery to the colon, were obtained.

One of the main problems associated with the application of native starches as film formers is related to their poor aqueous solubility. It is not possible to have a starch solution in room temperature. This and the lack of proper plasticizer systems results in difficulties in film coating process and in a poor storage stability of the final film coatings.

It is an object of the present invention overcome these problems by providing a method for preparing an aqueous coating dispersion of starch having good stability during storage and usability in the room temperature and at the same time good film-forming properties. The films prepared using the aqueous coating dispersion of starch according to the invention have satisfactory mechanical strength properties.

The method for preparing an aqueous coating dispersion of starch of the present in- vention is characterized in that it consists of the following steps: (1) heating a mixture of starch and water, (2) cooling the mixture down to 30 - 50°C, preferably to about 40°C, (3) precipitating with alcohol, (4) filtering and (5) dispersing the filtrate into water.

In the step (1) of the method of the present invention, the mixture is preferably heated to over 150°C, more preferably to about 160°C. In the step (3), preferably 97% ethanol is used and the adding ratio of 97% ethanol to the mixture is preferably about 1:1.

The starch used for preparing the aqueous coating dispersion of starch according to the present invention is preferably a so-called high-amylose starch, which contains preferably at least 50% of amylose. It can be for example high-amylose corn starch.

An aqueous coating dispersion prepared by the method according to the invention may be subsequently plasticized. Preferably plasticizing is done with plasticizer mixture of glycerol and sorbitol and more preferably with a plasticizer mixture con- taining 50% of glycerol and 50% of sorbitol. The plasticizer mixture content may be in a ratio of about 1 : 1 with respect to the starch content.

It is possible to add any pharmaceutically acceptable excipients or additives to the dispersion. Examples of these are preservatives or protective agents for microbi- ological and physical stability.

The aqueous coating dispersion of starch prepared by the method according to the invention may be used in coating substrates such as pharmaceuticals, food, agricultural seeds and the like. These coating dispersions are well adapted for coating pharmaceutical compositions containing an active agent and in that use spraying technique may be used.

The method of plasticizing explained above may be used also in other types of starch containing pharmaceutical coating compositions. This plasticizing method gives very good stability to the product.

The present invention is now explained in detail by referring to the attached figures and examples. These examples are only used to present some of the possible embodiments and are not intended to limit the scope of the invention.

Figure 1. Appearance of the Hylon VII films prepared from aqueous dispersion (stored for 2 months at 25°C, 60% RH).

Figure 2. Wide-angle X-ray scattering (WAXS) diffraction patterns of aqueous dispersions of Hylon Nil precipitated in different temperatures (10°C, 40°C and 70°C).

Figure 3. Appearance of Hylon VII film-coated tablets prepared in an instrumented side- vented drum-coating apparatus.

Figure 4. Appearance of the fresh Hylon VII films and the respective films stored for 9 months (25°C, 60% RH).

Figure 5. AFM images (topography) of the fresh Hylon VII films and the respective films stored for 9 months (25°C, 60% RH).

Figure 6. AFM images (phase diagram) of the fresh Hylon VII films and the respective films stored for 9 months (25°C, 60% RH). Figure 7. WAXS diffraction patterns of the fresh Hylon VII films and the respective films stored for 9 months (25°C, 60% RH and 40°C, 75% RH ).

Figure 8. Optimisation of Hylon VII film coating process of tablets: Effect of drum temperature and pump rate on the appearance (smoothness) of the film-coated tab- lets - Key: The lower values indicate smoother film coat.

Figure 9. Optimisation of Hylon VII film coating process of tablets: Effect of drum temperature and pump rate on the mechanical strength of the film-coated tablets.

Figure 10. Optimisation of Hylon VII film coating process of tablets: Effect of drum temperature and pump rate on the dissolution of the film-coated tablets - Key: The lower values indicate slower drag release.

Example 1

Method of preparation and characteristics of aqueous coating dispersion

The starch used was a native corn starch (Hylon VII, National Starch, Germany), in which the amylose content is 70% and the amylopectin content 30%. Sorbitol (Ph.Eur.) and glycerol (85%) (Ph.Eur.) were used as plasticizers, and purified water as a medium for film coating.

Native corn starch and purified water were blended (100 rpm) for preparing 2% mixture (500 ml). The mixture was heated in a reactor (160°C / 4 bar). The chamber was gradually cooled to 95°C and the hot solution was subsequently cooled in an ice bath to the aimed temperature. As the proper temperature was reached, 97% ethanol was slowly added to the solution in ratio of 1:1 (100 ml/min) with continuous blending. The suspension was blended with a magnetic stirrer for one hour after the ethanol addition. The following day, the suspension was filtered after which water was added to get the wanted concentration.

The precipitates were measured 24 hours after precipitation. The samples were measured by means of wide-angle X-ray scattering (WAXS). The WAXS experiments of the samples were performed in symmetrical reflection mode with CuK_α radiation (1.54 A). The angular range was from 2° to 60° (at 2fheta) with the steps of 0.02° and the measuring time was 20 s/step at all measurements. The size analysis was conducted with a laser diffraction apparatus (Malvem Instruments, UK). The measurements were performed in liquid (ethanol). All measurements were made 24 hours after precipitation and they were made in triplicate.

When ethanol was slowly added to an autoclaved starch solution there was no marked change until the alcohol concentration reached 38-40%. When the concentration reached 45% the starch was completely flocculated.

The assumption before conducting the study was that, the faster the stirring is at the ethanol addition, the smaller particles of the internal phase would develop. This was proven wrong, since as the solution was stirred with an Ultra Turrax, small yellow- ish particles not able to form a film were composed (Table 1). The cooling rate was also of importance for the formed precipitant. Too quick cooling did not give the precipitant a film forming property (Table 1). Finally the temperature was of major importance: ethanol addition at 10°C (A), 30°C, 50°C, and 70°C (C), did not give film-forming properties, while addition of ethanol at 40°C (B) did (Table 1). The film prepared from the native com starch dispersion (B) was translucent and clear to its appearance (Figure 1), and it was flexible and non-sticky when handled.

Table 1 Testing of various precipitation conditions for preparing an aqueous coating dispersion.

Exp. Temperature Cooling conditions Mixing procedure during pre- cipitation

70°C No ice bath, no mixing Ultra Turrax homogeniser

2. 10°C Heavy ice bath, mixing Ultra Turrax homogeniser

3. 6°C Heavy ice bath, mixing Magnetic stirring (200 rpm)

4°C Heavy ice bath, mixing Magnetic stirring (200 rpm)

20°C Heavy ice bath, mixing Magnetic stirring (200 φm)

6. 10°C Heavy ice bath, mixing Magnetic stirring (200 rpm)

7. 30°C Heavy ice bath, mixing Magnetic stirring (200 rpm)

30°C Ice bath, no mixing Magnetic stirring (200 rpm)

9. 40°C Ice bath, no mixing Magnetic stirring (200 rpm)

10. 50 °C Ice bath, no mixing Magnetic stirring (200 φm)

The precipitate made at 10°C was totally amoφhous, while the precipitates made at 40°C and 70°C showed some crystallinity (Figure 2). The precipitate made at 40°C showed, however, less crystallinity. Although amylose-ethanol crystalline com- plexes of Vh-type can be formed under certain conditions (Le Bail et al. 1995), in our study ethanol did not form a complex with amylose when the ethanol was added. The ethanol addition at the temperature of 40°C produced an essentially amoφhous precipitate, which easily produced a film.

The particle size was the smallest for the (C)-dispersion. However, there was not a great difference to the (B)-dispersion (Table 2). The (A)-dispersion, though, differed clearly from (B) and (C) with a much larger particle size (Table 2).

Table 2 Particle size of suspensions made in different temperature (n=3)

(mean+SD).

Example 2

Composition, method of preparation and characteristics of free films

Materials and preparation of film forming dispersion as described in Example 1. The temperature for the ethanol addition was 40°C.

For preparing free films, glycerol and sorbitol were added as plasticizers in the aqueous starch dispersions. The glycerol and sorbitol content was both 50% of the native com starch content. Thus, the total plasticizer content was 100% of the polymer content. The plastizicers were blended with the dispersion for 2 hours before casting the films. Eight grams (8.0 g) of a 5% native corn starch dispersion was poured onto the hot Teflon^® plates and put into a oven at a temperature of 70°C. The films were removed approximately after 2 hours from the Teflon^® plates. Effects of mixing time of the plasticizers on formation of free films are presented in Table 3. Table 3 Formation of Hylon VII -films prepared from aqueous dispersion.

* time period after the precipitation / mixing time of the plasticizers

The free films were held at 25°C and 60% RH for 2 days (initial). The thickness of the films, measured by a digital micrometer (Sony U30-F, Sony Magnescale inc, Japan), was an average of three points. A typical film thickness was 120 μm. The films were cut into suitable size and put onto glass bottles with calcium chloride (CaCl₂) and immediately sealed with metal rings. The bottles were held at 25 °C and 60% RH and were weighed several times during 28 hours. The test were performed in triplicate. The correlation of all the slopes were > 0.999. The water vapour transmission constants were calculated as follows:

P = (W x L) / (A x T x ΔP),

where P is permeability constant (g/cm mm Hg/24 h), W is grams of water diffusing through the film having thickness L and area A, T is the time in hours during which water diffuses, and ΔP is the vapour - pressure difference across the film (24.6 mmHg) at 1 atm when the water vapour pressure in the bottle was assumed to be dry (0 mmHg).

The tensile strength of the film, 5 MPa (Table 4) was comparable to that of the Hylon Vll-solution film - 4 MPa. The tensile strengths were not very high perhaps due to the unorthodox plasticizer level.

The elongation (%) at break for free films prepared of Hylon Vll-dispersion was almost the double, 26% (Table 4) compared to the films prepared of Hylon VII- solution (14%). The elongation (%) for films prepared of dispersions are for example for HPMCAS 3% and CAP 9% (Nagai 1997). Thus, the Hylon VII films, with the tested plasticizer level, had greater plasticity than the above mentioned film formers.

The values for the WVT of the fihns prepared of the Hylon Vll-dispersion, were a little less (3.30E-05 g/cm mm Hg 24 h) (Table 4), than those for the films prepared from the Hylon VII solution (approx. 2.00E-05 g/cm mm Hg 24 h). Still, the transmission results for the free films were higher than those for hydroxyprophyl methylcellulose films (5.91E-06 g/cm mm Hg 24 h).

Table 4 Mechanical properties and water vapour transmission (WVT) of Hylon VII films prepared from aqueous dispersion (n = 3-6).

Example 3

Film coating of tablets

Materials and preparation of film coating dispersion as described in Example 1.

For application and testing of the plasticized Hylon VII dispersions for actual film coating of tablets, a laboratory-scale instrumented side- vented drum-coating apparatus (Thai coater, model 15, Pharmaceuticals and Medical Supply Ltd Partnership, Thailand) was used. For film coating, 1000 g of tablet cores were weighed. The pneumatic spraying pressure was 300 kPa, the dram temperature 50°C, and the rotating speed of the pan 7.0 φm. After the coating the tablets were dried for 5 minutes at 50°C in the drum-coater. Thereafter the tablets were kept at room temperature (25°C/ RH 60%) for at least 24 hours before the film-coated tablets were studied.

The responses evaluated were appearance of the film-coated tablets (with stereo microscope), weight increase (n = 20), radial breaking strength (Erweka Multitester; n = 20), and dimensions of the tablets before and after film coating measured by a micrometer (Sony Inc., Japan; n = 10).

No drawbacks nor difficulties were met in the film coating procedure of tablets with aqueous Hylon VII dispersion.

Appearance

As seen in figure 3, the film-coated tablets are covered with a smooth and continuous film. No significant film defects (i.e. blistering, peeling, splitting etc.) can be seen. The appearance of the film-coated tablets could be improved if the process conditions were optimised. The preliminary results suggest that the coating tem- perature of 50°C and the pump rate of 7-8 g/min are beneficial; the levels of below or above these values impair the quality of the film coating.

Example 4

The starch used was a native corn starch (Hylon VII, National Starch, Germany), in which the amylose content is 70% and the amylopectin content 30%. Sorbitol (Ph.Eur.) and glycerol (85%) (Ph.Eur.) were used as plasticizers, and purified water as a medium.

The Hylon VII solution was prepared in a high-pressure reactor. The suspension was heated under continuously blending (100 φm) to 160 ± 1°C (pressure 4 bar), after which the solution was cooled to 95 ± 2°C and removed. The prepared solu- tion was heated continuously to keep the temperature at 80 ± 2°C. The final Hylon VII content of the solution was 5% and the plasticizer content was in ration of 1:1 with respect to the polymer content (Hylon VII). The plasticizers glycerol (50%) and sorbitol (50%) was added and mixed with the solution. The films were prepared immediately thereafter. The solution was poured into Teflon moulds, which were kept in an oven for approximately two hours at 70°C until the edge curling occurred and the films were allowed to dry.

The mechanical strength of the films were tested with a material testing machine (Lloyd LRX, Lloyd instruments Ltd., Great Britain). The films were held in 25°C and 60% RH for 24 hours (initial) and for nine months before testing. The rectangu- lar films were measured before testing. The thickness was measured with a digital micrometer (Sony U30-F, Sony Magnescale inc, Japan) and the width with a millimetre ruler. The films were cut into strips and put to the material testing machine where the grips were 40 mm from each other. The extension speed was 10 mm/min. The stress-strain curves were recorded, and the tensile strength at break and elongation (%) were measured

The stress-strain properties are a sensitive measure of the ageing of pharmaceutical films. As seen in Table 5, the elasticity of the Hylon VII films was not changed during the storage period of 9 months. The tensile strength of the present films increased to some extend during the storage.

Table 5 Effect of time on mechanical properties of free 5 % Hylon VII films (mean ± S.D., n=3).

The films with only one plasticizer (i.e. sorbitol or glycerol) and with other plasticizer levels were also prepared. Sorbitol/glycerol contents of 25%, 50% and 100% were used. However, these films could not be tested after 9 months (in 25 °C 60% RH), due to remarkable changes of the films. The films had shrank and were hard and wavy and in some of the films the aging had led to spontaneously formed cracks. From some of the films sorbitol had crystallised on the surface and from the films with > 50% glycerol the glycerol were as droplets on the surface of the films.

Example 5

Materials, and preparation of film coating solutions and free films as described in Example 4.

For testing the water vapour transmission (WVT) the films were held at 25 °C and 60% RH for 2 days (initial) and subsequently for nine months before experiments. The thickness of the films, measured by a micrometer (Sony U30-F, Sony Magnescale inc, Japan), was an average of three points. A typical film thickness was 120 μm. The films were cut into suitable size and put onto glass bottles with calcium chloride (CaCl₂) and immediately sealed with metal rings. The bottles were held at 25°C and 60% RH and were weighed several times during 28 hours. The test were performed in triplicate. The correlation of all the slopes were > 0.999. The water vapour transmission (WVT) constants were calculated as in Example 2. The measured WVT of the Hylon VII films were around 4^"5 g/cm mm Hg 24h at 60% RH (Table 6). The WVT of the Hylon VII films were higher compared to fresh hydroxy-propylmethyl cellulose (HPMC). The Hylon VII films were, however, stable in respect of WVT. The WVT of the Hylon Vll-films did, namely, not change during nine months of storage (Table 6).

Table 6 Effect of time on WVT of Hylon Vll-films. Correlation > 0.999 (Mean ± S.D., n=3-6).

Water vapour transmission (g/cm mm Hg 24h), mean ± S.D.

Hylon VII, initial free films 4 Λ .6 c£6.-Ec- n05c J ±.

Hylon VII, free films stored 4.34E-05 ± 0.27E-05 9 months (25°C/ RH 60%)

HPMC, initial free films 5.91E-06 ± 4.41E-06

Example 6

Materials, and preparation of film coating solutions and free films as described in Examples 4 and 5.

For testing the internal structure (i.e. crystallinity) and moφhology of the starch films, the films were held at 25°C and 60% RH for 2 days (initial) and subsequently for nine months at 25°C/ RH 60% or at 40°C / RH 80% before testing. The samples were measured by means of wide-angle x-ray scattering (WAXS). The WAXS experiments of the samples were performed in symmetrical reflection mode with CuK_α radiation (1.54 Angstroms). The angular range was from 2° to 60° (at 2theta) with the steps of 0.02° and the measuring time was 20 s/step at all measurements.

Atomic force microscope (AFM) analysis was conducted with Park Scientific In- straments Autoprobe CP (Thermomicroscopes, USA) with a Multitask- measuring head. For the phase images the AFM was equipped with a M.A.P.®-module, which enables measurements of force moulding and phase separation signals.

Visually observed, the films stored for nine months were the same as the freshly prepared films (Figure 4). To get a closer look at the appearance of the Hylon VII films AFM was used. The topography (Figure 5) and the phase diagram images (Figure 6) in our study of fresh films and films stored for 9 months (25°C, 60% RH) were very alike. In the micrographs can two areas be distinguished, a smoother area and a more rough area. In the rougher there is probably a higher content of starch molecules and in the smoother areas a higher content of plasticizer molecules. In these highly plas- ticized amylose rich starch films there are phase separation in the fresh films. How- ever during storage the phase separation do not increase.

The starch molecules forms a B-type crystallinity in the Hylon films, and the respective B-type crystallinity was observed in the stored films as well. WAXS diffraction pattern of fresh films closely resembled the model intensity curve of ortho- rhombic starch where a = 18.5 A, b = 18.5 A, c = 10.4 A, α = 90°, β = 90° and χ = 120° (Figure 7). However, the intensities of the reflections of the diffraction patterns of the film and the model intensity curve did not match perfectly due to preferred orientation of the film.

The diffraction patterns of the 9 months old Hylon VII films were near the diffraction pattern of the fresh films but the diffraction patterns included also differences (Figure 7). All reflections of the fresh Hylon VII films are seen in the diffraction patterns of 9 months old films but the intensities of the reflections were different. The intensity of the reflection 311 of fresh film is stronger than in the diffraction patterns of old films. This indicates that the crystals of the films have turned and the films have changed more isotropic. The amoφhous background of the diffraction patterns, of old films were also different. The diffraction pattern of the Hylon VII films, which were kept at 60% RH included more the features of the amoφhous glycerol than the films, which were kept at 75% RH. The reflections of the diffraction pattern of films kept at 75% RH, were also stronger than these of the diffraction pattern of films kept at 60% RH. The water content was also higher in the films at 75% RH, which formed the diffraction pattern. Part of the water molecules are also probably situated in the starch crystals in the films at 75% RH, which also explains the stronger reflections. Some of the water molecules are in the amoφhous component, which changes the form of the amoφhous background.

The estimation of the crystallinity was based on the assumption that the experimen- tal intensity curve is a linear combination of the intensity of a crystalline and an amoφhous component. The crystallinities of the films were estimated by fitting the intensities of crystalline and amoφhous components to the experimental intensity curve. The experimental intensity curve from which the Bragg peaks were subtracted was used as the amoφhous model intensity curve and the crystalline model intensity curve consisted only of the diffraction peaks. The ageing of starch films may be explained by recrystallisation of starch. In this study the crystallinity of the Hylon films did not increase during storage (Table 7). The crystallinity of fresh Hylon VII films was 24%. The crystallinity of the films stored for nine months at 60% RH were 25% and the crystallinity of the films stored for nine months at 75% RH was decreased to 21% indicating that some water molecules are in the amoφhous background outside the crystals.

Table 7 The effect of time and storage conditions on crystallinity and crystal size of sorbitol-glycerol-Hylon VII films.

The average crystal size of the films was estimated by means of the well-known Scherrer formula from the width of the reflection 211. The average size of the fresh Hylon VII films was 65 A. The average crystal size increased to 68 A for Hylon VII films stored at 60% RH and to 72 A at 75% RH, which supports the assumption that some water molecules goes to the crystals.

Example 7

Materials, and preparation of film coating solutions as described in Examples 4, 5 and 6.

For application and testing of the plasticized Hylon VII solutions for actual film coating of tablets, a laboratory-scale instrumented side- vented drum-coating apparatus (Thai coater, model 15, Pharmaceuticals and Medical Supply Ltd Partnership, Thailand) was used. Three independent variables were studied and optimized by using a face centred composite design (CCF) as an experimental design: temperature in coating drum (XI), plasticizer content (X2), and spray rate of coating solution (X3). For film coating, 900 g of tablet cores were weighed. The pneumatic spraying pressure was 300 kPa, the rotating speed of the pan 7 φm. After the coating the tab- lets were dried for 5 minutes in the dram-coater. Thereafter the tablets were kept at room temperature (25 °C/ RH 60%) for at least 24 hours before the coated tablets were studied. The responses evaluated were appearance of the film-coated tablets (optical image analysis), weight increase (n = 20), radial and axial breaking strength (Multitester and Lloyd Material Testing device; n = 20), and dimensions of the tablets before and after film coating measured by a micrometer (Sony Inc., Japan; n=10). In vitro drag release was studied using a basket method (USP XXIII) with a phosphate buffer solution pH 1.2 (USP XXIII) as a dissolution medium (Sotax AT6, Switzerland; n=6).

The film coating procedure of tablets with aqueous Hylon VII seems to be rather sensitive to process conditions and less sensitive to material variables (i.e. plasti- cizer). Based on the preliminary tests, a number of process conditions could be neglected (i.e. the highest amount of plasticizer and the lowest drum temperature combined with the highest pump rate).

Appearance

In figure 8, the smaller values for the light intensity indicate better appearance (smoothness) of the film coat. The smoothest films were obtained with lower pump rate. If the drum temperature is high (i.e. 70°C), the pump rate does not have so much effect on the smoothness. The effect of amount of plasticizer on the smoothness was non-linear. The appearance of the film-coated tablets can be improved if the plastizicer contents (sorbitol / glycerol) above 33% but under 100% are used; the amounts below or over these values impair the quality of the film.

Mechanical strength

The effects of dram temperature and pump rate on the mechanical strength of the Hylon VII film-coated tablets are shown in figure 9. If low drum temperatures (i.e. below 60°C) are used, the pump rate have a clear negative influence on mechanical strength of the film-coated tablets. In higher temperatures (i.e. 60-70°C) the pump rate does not have any influence on the mechanical strength of the Hylon VII film coatings. Increase in the amounts of plasticizer results in weaker film coatings of the tablets.

Dissolution of film-coated tablets

The effects of drum temperature and pump rate on the dissolution of film-coated tablets are shown in figure 10. Dissolution of film-coated tablets seems to be slightly slower if higher drum temperatures instead of lower, are applied. The film- coated tablets, however, comply the requirements given in the relevant pharmaco- poeias. If low drum temperatures and high pump rate are used, the dissolution of the tablets is very fast, but some difficulties with coating process can be met.

In summary, it can be concluded that drum temperature and flow rate of coating solution (i.e. pump rate) are important process parameters affecting the quality of the Hylon VII film-coated tablets. High coating temperatures (70°C or above) are not suitable for film-coating with Hylon VII, whereas the temperatures from 50°C to 70°C seem to produce film coatings with better appearance. The lowest flow rate (2.5 g/min) of coating solution produces tablet film-coatings with a poor appearance, whereas higher flow rates (i.e. from 2.5 to 4 g/min) give films with better quality.

References

Bader and Goritz, Starch/Starke, 46 (6), 229-232 (1994)

Bader and Goritz, Starch/Starke, 46 (7), 249-252 (1994)

Kudera, US 2,973,243 (patented February 28, 1961)

Langlois and Wagoner, Production and use of amylose in Starch: Chemistry and Technology, vol. II, Whistler and Paschall (ed.), Academic Press, 451-497 (1967)

Le Bail et al., Starch/Starke 47 (6), 229-232 (1995)

Lourdin et al., Carbohydr. Polym., 27, 261-270 (1995)

Milojevic et al., J. Control. Rel., 38, 75-84 (1996)

Muetgeert and Hiemstra, US 2,822,581 (patented February 11 , 1958)

Nagai et al., Aqueous polymeric coatings for pharmaceutical dosage forms, 2^nd ed. McGinity J.W. (ed.), 177-225 (1997)

Palviainen et al., Pharm. Dev. and Technology, submitted for publication (2000)

Rindlav-Westling et al., Carbohydr. Polym., 36, 217-224 (1998)

Unbehend and Sarko, J.Polym.Sci, 12, 545-554 (1974)

Wolff et al., Industrial and Engineering Chemistry, 43 (4), 915-919 (1951)

Claims

1. A method for preparing an aqueous coating dispersion of starch, characterized in that it consists of the following steps: (1) heating a mixture of starch containing at least 50% of amylose and water to over 150°C, preferably to about 160°C, (2) cooling the mixture down to 30 - 50°C, preferably to about 40°C, (3) precipitating with ethanol, (4) filtering and (5) dispersing the filtrate into water.

2. A method according to claim 1, characterized in that in the step (3) 97% ethanol is used.

3. A method according to claim 2, characterized in that the adding ratio of 97% ethanol to the mixture is about 1:1.

4. A method according to any of claims 1 to 3, characterized in that the starch is high-amylose com starch.

5. An aqueous coating dispersion of starch, characterized in that it is prepared by the method of any of claims 1 to 4.

6. An aqueous coating dispersion of claim 5, characterized in that the dispersion is subsequently plasticized.

7. An aqueous coating dispersion of claim 6, characterized in that the dispersion is subsequently plasticized with plasticizer mixture of glycerol and sorbitol.

8. An aqueous coating dispersion of claim 7, characterized in that the plasticizer mixture contains 50% of glycerol and 50% of sorbitol.

9. An aqueous coating dispersion of claim 7 or 8, characterized in that the plasticizer mixture content is in a ratio of about 1 : 1 with respect to the starch content.

10. An aqueous coating dispersion of any of claims 5 or 9, characterized in that pharmaceutically acceptable excipients or additives, such as preservatives or protec- tive agents for microbiological and physical stability, are added to the dispersion.

11. Method of coating substrates such as pharmaceuticals, food, agricultural seeds, substrates of chemical industry and the like, characterized in that the aqueous coating dispersion of starch of any of claims 5 to 10 is used.

12. Method of coating substrates of claim 11, characterized in that the substrates to be coated are pharmaceutical compositions containing an active agent.

3. Method of claim 11 or 12, characterized in that spraying technique is used.