IL42312A - Pharmaceutical formulations comprising microencapsulated ampicillin trihydrate or amoxycillin trihydrate - Google Patents

Description

ικιητπ'ηο J' X'SBK o*/*a»n m.npn 'wsn o-nx-^i niTyt monaa:. tnnn»n» 7* x»opiBK Pharmaceutical formulations comprising microencapsulated ampicillin trihydrate or amoxycillin trihydrate and their manufacture BEECHAM GROUP LIMITED C: 40485 compositions. Mor to powders compris trihydrate or amoxycillin trihydrate and to a process for the manufacture of such powders.

When used herein with respect to the novel pov/ders of the invention, the term "pander" means a dustless, free-f lowing powde .

VJhen used herein the term "dustless" when applied to a powder means that the powder is substantially free from microcapsules of diameter less than 50y. Normally and preferably, dustless p ders contain no microcapsules of diameter less than 50y. Under ideal conditions such dustless powders contain no microcapsules of diameter less than 75M but a powder vail for almost all practical, perposes be considered to be dustless if it contains less than 2% of microcapsules of diameter less than 75y.

When used herein the term "free- lowing" when applied to a powder means that the powder has an angle of repose less than 40°.

When used herein the term "microcapsule" means a particle composed of an outer generally porous shell of polyvinylpyrrolidone with an inner core of fine particles.

The core may contain small quantities of air and interspersed strands of polyvinylpyrrolidone. The shell material may be continuous or may contain depressions or "blow holes" giving access to the core from the outside^ Thus a powder comprising microencapsulated ampicillin trihydrate or amoxycillin trihydrate will contain microcapsules comprising ampicillin trihydrate or amoxycillin trihydrate within a shell of polyvinylpyrrolidone.

When used herein the term "medicament" means an organic ampicillin trihydrate or amoxycillin trihydrate.

When used herein the term ''conventional phannaceut cal excipients" means excipients used in phan.nac.euti cal formulations to improve the quality of the formulation or to increase the ease of preparation of the formulation and includes binders , lubricants , flavours, colours, dis integrants and the like. When calculating the percentage of such excipients present, the coating agent present in the i re die amen t containing microcapsules is not included.

When used herein percentages are calculated on a weight /weig t basis unless otherwise stated.

The processing of ampicillin trihydrate or amoxycillin trihydrate from the initial production of the compound to the formulated product ready for use normally involves a milling stage. Milling is included to reduce the particle size of the ampicillin trihydrate or amoxycillin trihydrate, to improve the drying rate of the material, to aid in blending operations, to increase the bioavailability of the ampicillin trihydrate or amoxycilli trihydrate from the formulation or for various other reasons. Unfortunately, if the milling operation is sufficient to reduce the average arapicillin trihydrate or amoxycillin trihydrate particle size to the desired range, then a small but -significant proportion of the trihydrate ampicillin/or amoxycillin trihydrate becomes sufficiently finely divided to form a disadvantageous dust. Unless extensive and inconvenient special handling techniques are used, generally some of the dust gets released into the atmosphere where it constitutes a health hazard and can lead to cross-contamination of active materials.

The health hazard from airborne particles is particularly high when people can become sensitized to the ampicillin trihydrate or amoxycillin trihydrate. Attempts to reduce the dust hazard by replacing the initial dry milling stage by a wet milling operation are not normally successful as this merely delays the formation of the dust to a subsequent drying or handling stage.

The handling properties, taste and stability of medicaments which are to be processed into tablets or capsules, may often be improved by mixing the medicaments with specific binders or lubricants before the medicament is slugged to form a tablet or capsule or by coating the medicament with a material which allows rapid disintegration of the dosage form in the stomach or intestines. For example , South African Patent No. 68/05560 describes. inter alia that tablets wherein ampicillin, hetacillin, oxacillin, cloxacillin or dicloxaclllln are mixed with polyethylene glycol and mannitol have more pleasant taste than those wherein the penicillins are mixed with a conventional binder; whilst German Patent Application Nos. 20584j'+ and 2ΐ4βΐγ4 disclose that coated medicaments which have good handling properties may be prepared by spraying a suspension of the medicament in a solution of the coating agent in a suitable solvent. Israel Patent 51^4^1 discloses inter alia that the stability and bio-availability of ampicillin trihydrate in compositions intended for intramuscular administration may be improved by coating the ampicillin trihydrate with hydrophilic and lipophilic surfactants.

We have now found that particles of ampicillin trihydrate or amoxycillin trihydrate when coated with polyvinylpyrrolidone by a spray dying process adapted to give microcapsules containing a very small percentage of polyvinylpyrrolidone and which are of particularly large particle size, have particularly advantageous properties. In particular the microcapsules are large, free flowing, possess good processing properties and have good stability Further these microcapsules of ampicillin trihydrate and amoxycillin trihydrate coated with very small percentages of polyvinylpyrrolidone have excellent direct compression properties. This is most surprising -as ampicillin trihydrate and amoxycillin trihydrate have very poor direct compression properties, they cannot be directly compressed into tablet form, and polyvinylpyrrolidone is not recognised as -being a good compression agent when used in small quantities.

It is also surprising that microcapsules containing ampicillin and amoxycillin in their trihydrate form may be produced a spraydrying process without losing their water of hydration particularly when the so^venfused in the spray-drying process is water.

These powders are novel and therefore form an im ortant aspect of this invention.

Accordingly, the present invention provides a powder comprising essentially of microcapsules having an average diameter of from ΙΟΟμ to 300μ with at least 90% of the microcapsules having diameters In the range 35μ to 450μ and which comprise 98% to 99.9% of ampicillin trihydrate or amoxycillin trihydrate coated by 0.1% to 2% of a coating agent.

The limits for the average diameter of the microcapsules are set at 100μ and 300μ because if the average diameter falls below this range the powder is likely to be dusty and if the average diameter is above this range the biovalability of the ampicillin trihydrate or amoxycillin trihydrate may be reduced.

The lower limit of 011% for the quantity of coating agent in the microcapsules is chosen because if smaller quantities of coating agent are used the microcapsules tend to be of poor quality. The upper limit of 2% is chosen in order to keep the costs of the process low and to ensure acceptable bPharmaceutical properties.

The interplay of the preceding factors result in a particularly suitable range of quantities of polyvinylpyrrolidone in the microcapsules being about 0.2% to 1%.

In order to ensure the dustless properties of the powder of the invention and at the same time retain the bioavailability of the medicament, at least 90% of the microcapsules should have diameters in the range 75μ to 450μ, more suitabl 95% of the microcapsules should have a diameter in this size range and preferably 99% of t3* ^ microcapsules should have diameters in this size range.

It is believed that suitable powders are comprised of microcapsules at least 80% of which have diameters between 100μ and 300μ. In general, microcapsules with such characteristics will have an average diameter of at least 150μ but less than 250μ, for example, from approximately 150μ to 225μ.

Generally, powders having particularly good bioavailability and versatility consist essentially of microcapsules comprising 99% to 99.8% ampicillin trihydrate or amoxycillin trihydrate and 0.2% to 1% polyvinylpyrrolidone which microcapsules have an average diameter between 150μ to 250μ, 95% having diameters between 75μ to 450μ and 80% of which have diameters between 10Oft to 300μ.

It is believed that frse-flowing, finely divided solids comprising microcapsules containing ampicillin trihydrate or amoxycillin trihydrate coated with from 0.1% to 2% of polyvinylpyrrolidone are novel. -It is surprising that microcapsules containing such small quantities of polyvinylpyrrolidone are of good quality and have good tabletting and other processing properties. Therefore, such free-flowing, finely divided solids are included within the invention.

Generally the most suitable of such free-flowing, finely divided solids comprise 95% to 100% of microencapsulated ampicillin trihydrate or amoxycillin trihydrate which microcapsules comprise 98% to 99.8% of ampicillin trihydrate or amoxycillin trihydrate and 0.2% to 2% of polyvinyl The powders of this invention may be prepared by s rs^ % drying a slurry comprising a suspension of ampicillin trihydrate or amoxycillin trihydrate in a solution of polyvinylpyrrolidone in a solvent.

Spray drying is a well understood process widely used in industry. However, microencapsulation of a *§-lactam antibiotic by means of spray drying has not found widespread use on a commercial scale. In those cases where spray drying has been reported as a suitable method of microencapsulation the microcapsules produced have always been relatively small so that the product has been dusty. This may be because only small spray driers have been used. Further, it does not appear to have been discovered that microcapsules may be prepared which contain very small percentages of coating agent and which are also dustless.

Furthermore, the products of the process of this invention have advantages over conventional raw materialsforms such as:- 1) The process produces large dustless, free-flowing powders. The powder is contained within the shell material during processing and the dust produced during mixing and handling operations is markedly reduced or eliminated. 2) Coated products containing thermolabile substances often retain the maximum potency. The conditions of production are mild and the stability characteristics of the product may be optimised. 3) The process control is precise. The residual solvent content can usually be maintained at a required level and the characteristics of the 4) The method can be incorporated as a last st&£» in the manufacturing process of ampicillin trihydrate or amoxycillin trihydrate. The centrifuged or filtered vet cake of the product may be reslurried in the polymer solution, homogenised and spray dried to produce the product.

The processing costs are frequently no greater than those of conventional methods of manufacture and the plant capacity can be adjusted within a large range to suit the product. 5) The spray dried powders may be designed to be suitable for compounding into tablets, capsules, pediatric syrups and other dosage forms.

The present invention also provides a process for the preparation of a pharmaceutical formulation which contains or is derived from a powder of this invention which process comprises forming a slurry of ampicillin trihydrate or amoxycillin trihydrate in a solution of apolyvinyl-pyrrolidone, and spray drying the slurry.

In order to produce a dustless powder, the microcapsules must have an average diameter greater than ΙΟΟμ. This can generally be achieved if the spray of slurry to be dried is composed of droplets substantially all of which have diameters in the range lOOu to lOOOy. Preferably, such droplets should have diameters in the range 150μ to 900μ. This is a particularly suitable size range of droplets as it often allows the production of microcapsules of an average diameter of about 150 to 250ywwhich is a suitable range of average diameter* In conventional manner, the ratio of the size of th ** microcapsule produced to the sire of the droplet formed is roughly proportional to the percentage of suspensed solids in the slurry.

Thus one aspect of the process of this invention comprises the formation of a slurry of ampicillin trihydrate or amoxycillin trihydrate in a solution of polyvinylpyrrolidone, dispersing the slurry as droplets substantially all of which have diameters of from ΙΟΟμ to Ιθθθμ into a spray drying cavity and collecting the resulting microcapsules in conventional manner and thereafter, if desired processing the microcapsules into standard dosage forms.

For reasons of economy, the amount of suspended solids is normally kept as high as compatible with the spray drying apparatus. Thus the suspended solids usually comprise 15% to 66% of the al-irry. In the present invention about 33% to about 60% often provides a satisfactory range, 40% to 55% is generally a particularly suitable range while frequently the best results may be achieved by using an approximately 45% to 50% suspension.

Thus in one preferred form this aspect of the invention provides a process comprising the formation of a slurry of ampicillin trihydrate or amoxycillin trihydrate in a solution of polyvinylpyrrolidone which slurry may contain 33% to 60% of suspended ampicillin trihydrate or amoxycillin trihydrate, dispersing the slurry as droplets substantially all of which have diameters of from 150yto 900μ into a spray drying cavity and collecting the resulting microcapsules in conventional manner.

If required, small amounts of anti-foaming agents sucjJ^ as octanol or de-floculants such as polyoxyethylene sorbitan monooleate ( ween 20 - Registered Trade Hark) may be added to the slurry.

The spray drying process of this invention is unusual in that the slurry to be spray dried cortains only small quantities of dissolved polyvinylpyrrolidone, for example, if total suspended solids plus total polyvinylpyrrolidone amount to 100% then the polyvinylpyrrolidone present will normally be only about 0.1% to 2%.

Thus one aspect of this invention provides a process which comprises forming a slurry of ampicillin trihydrate or amoxycillin trihydrate in a solution of polyvinylpyrrolidone which slurry may contain 33% to 60% of suspended solids as hereinbefore described and in which the dissolved polyvinylpyrrolidone forms 0.1% to 2% of the total weight of suspended solids plus polyvinylpyrrolidone, spray drying the slurry and collecting the resulting microcapsules in conventional manner.

It is more suitable that the slurry contains 0.2% to 1% of dissolved F«l.?vinylpyrroaidone expressed as a percentage of the total weight of suspended solids plus polyvinylpyrrolidone.

The slurry to be spray dried may be made in any suitable solvent such as water, ethanol, propanol, chloroform, methylene chloride, acetone, methylethylketone, methyl acetate, ethyl acetate, methanol, tricHoroethylene, tetrachloroethylene , carbon tetrachloride or like solvents or homogeneous mixtures of such solvents. Obviously, since or amoxycillin trihydrate has low solubility and ^ preferably to those in which they are insoluble or substantially insoluble.

Normally, the solubility of the medicament, is less than 15% and preferably less than 10%, for example, below 5% at the tempe atures used.

The choice of solvent is further limited to those which dissolvejpolyvinylpyrrolidone . The solvent should be one in which polyvinylpyrrolidone is at least 10% soluble at the temperature of forming, storing and spraying the suspension to be spray dried and preferably at least 20% soluble at that temperature. Microcapsules of good quality are generally most easily prepared if the coating agent is at least 30% soluble in the solvent used.

The ampicillin trihydrate or amoxycillin trihydrate present in the slurry may already be finely divided. However, if this is not the case, it will be necessary to include a wet milling operation to reduce the particle size of the suspension before the slurry is spray dried. Any convenient conventional method may be used for this purpose Before the slurry is spray dried it is normally beneficial to homogenise it in conventional manner.

The process of the invention may take place in any conventional large spray drier but the best results are often obtained from the kind of conventionaly spray drying equipment shown in Figure 1. Although large spray driers of this kind are not generally used in the pharmaceutical industry they are well known in other industries where large scale drying apparatus is used. For the present invention the spray drier may be operated in a conventional manner wherein the various operating parameters such as inlet and outlet temperatures, pumping pressures, liquid flow rate, gas flow rate, atomiser design and the like affect the nature of the product in conventional manner.

When using an open cycle drying system of the sort shown in Figure 1, the homogenised slurry (1), is stored in a tank (2) in which it is agitated by the homogenisor (3), until it is pumped by the high pressure pump (¾) to the atomiser (5) at the top of the spray drier. The atomiser (5) is generally of the nozzle type although spinning disc atomisers may be used on wide spray driers. Ihe nozzle atomiser (5), sprays droplets into the drying cavity (6) where the droplets dry in and with a co-current air-flow which originates at the outlet (7). This drying air has been heated to the desired temperature in an air heater (8) before being pumped to the outlet (7). After leaving the outlet (7), the heated air descends through the drying cavity (6) into the bussle (9) where it turns upwards and leaves through the vents (10) from where it passes via a cyclone (11) to the exterior (12).

As the air descends inside the dryer, the liquid present in the droplets evaporates to leave microcapsules; this process is completed by the time the air and the materials suspended in it reach the bussle (9). As the air turns upward in the bussle, it precipitates most of the microcapsules which fall through the opening (13) at the bottom of the bussle (9) into a screen system (14) u ich separates the microcapules in the desired size range from the fines. Ihe desired microcapsules and fines are respectively deposited in the collection vessels (15) and (16). Any microcapsules present in the air leaving via the cyclone (11) are precipitated and separated into microcapsules of the desired size range and fines by a screen system (17). The desired microcapsules and the fines are respectively deposited in the collection vessels (15) and (l8).

The fines generally represent 5% to 10$ of the spray dried product and may be added to the initial slurry for recycling thereby minimising losses.

If it is desired to use a solvent which is to be recollected after passing through the apparatus, a condensor system may be included in the apparatus at some point after the cyclone (11). In such conventional closed-cycle spray drier, the heated air is normally replaced by heated solvent vapour.

Both open-cycle and closed-cycle spray driers are equilibrated and operated in conventional manner.

Suitable parameters for an open-cycle spray drier are generally (water as solvent): Spray dryer height 6- 20 metres Spray Dryer Chamber diameter 1 - 3 metres Feed rate of suspension 25 -200 lthr.

Atomizer nozzle diameter O.5-I.5 mm Atomizer nozzle pressure 5 -15 kg/cm^ Rate of air flow 750-1200 kghr.

Inlet temperature 150-250°C Outlet temperature 50-120°C Suitable parameters for a closed-cycle spray dryer are generally: Spray dryer height 6-20 metres Spray dryer chariber diameter 1- 3 metres Feed rate of suspension 25-200 lthr.

Atomizer nozzle diameter 0.5-1.5 mm Atomizer nozzle pressure 5-15 kg/cm2 Dry gas, orifice plate pressure drop 70-120 mm WG Inlet temperature 60-130°C Outlet temperature 40-80°C Condenser temperature 0-30°C Once the desired microcapsules are isolated they may be stored prior to use or they may be used at once to manufacture dosage forms suitable for administration to animals including man.

Such dosage forms may contain conventional pharmaceutical carriers.

In the foliating Examples, unless otherwise stated, a Nino TOWER SPRAY DRIER was used. The drier is similar to that shown schematically in Figure 1 and is approximately 12 meters high and 1.75 meters in diameter. Such apparatus is of an industrially used dosage and was made by Miro Atomizer Limited, Copenhagen, 305 Gladsaxevej, DK-2860 Sobeborg, Denmark.

The coating agents A and B of the Examples are as follows :- Letter Coating Agent Trade Supplier Name (If Any) A Polyvinylpyrrolidone Plesdone K29-32 G.A.F B Polyvinylpyrrolidone Kollidon 25 B.A.S.F.

Example 1 Preparation of Microencapsulated Aapicillin Trihydrate (a) Formation of Slurry A solution of polyvinylpyrrolidone (0.11 kg) in de-mineralised water was prepared in a suitable vessel using a Silverson LZR mixer with standard emulser attachment., A suspension of aapicillin trihydrate (22 kg), obtained from a wet cake of the material taken from a standard commercial production batch, in demineralised water was prepared in a second vessel using a Silverson mixer and turbo-stirrer.

The polyvinylpyrrolidone solution was added to the ampicillin trihydrate suspension, mixed and then defoamed with a snail quantity of octanol. The weight of water present was 27 kg. The suspension was then pumped to a feed tank via a 0.3 EUD screen. The suspension was kept stirred in the feed tank to ensure an even distribution of particles. . (b) Tower O eration The suspension from the feed tank was pumped through a nozzle atomiser at about 18 kg/hr. The nozzle orifice diameter was set at 0.9 nm» the spray angle of the nozzle o 2 was set at 45 and the nozzle pressure at 9- kg/cm . A concurrent air flow was pumped through the spray dryer at - .-, ' 800 kg/hr. and the temperature of the air adjusted to give an inlet temperature of 140° and an outlet . temperature of 68-70°.

The encapsulated powder was collected from the bottom of the tower in a discharge hopper and a cyclone . separator. In general, 20£o to 25/* of the products were recovered in the cyclones and 75/» to 80 were collected from the chamber. There was no observable powder present in the exhaust gas leaving the stack.

The product was screened in the apparatus prior to collection ■ to remove particles below 75μ (5° to lOj'i) and the encapsulated powders were stored for evaluation and pharmaceutical processing The spray dried, powders consisted of particles composed of an outer porous shell of polyvinylpyrrolidone with an inner core of fine anpicillin trihydrate powder. The core contained small quantities of air and interspersed strands of polyvinylpyrrolidone. The microcapsules produced appeared to have continuous coats free of 'blow holes*.

Properties of the Product of Ezgsle 1 (i) Moisure content : 13.75» The moisure content of the product could be maintained accurately at any desired level by controlling inlet and outlet temperatures of the spray drier. The result quoted is an average of several determinations because the spray drier was not operating under equilibrium, conditions as only small samples were used. Under equilibrium conditions and when the fractions from the drying chamber and cyclone are continuously removed, the residual moisture may be controlled to within - 0.5 . (ii) Potency : The potency of the raw material and the micro-encapsulated product were effectively the same. (iii) Stability.

The accelerated stability results obtained indicated that the microencapsulated β-lactam antibiotic is likely to have considerably longer shelf life than the untreated raw material. The TQQ is the time in hours at 80°C required for the material to undergo 10¾£ decomposition. For Example 1 the for the microencapsulated material was at least 3 tii:e3 as long as for .the raw material. (iv) Particle , Size Distribution: In general, the particles obtained from the cyclone fraction are smaller than those obtained from the drying chamber fraction and there is usually about fcur times as much product collected from the chamber fraction as from the cyclone fraction. Figure 2 shows the size distributions in the powders obtained by mixing cyclone and chamber fractions prior to separation of the fines, It has been shown that - (ay the average microcapsule size of each product lies between 150μ and 20ϋμ (b) 3efore separation, ¾* to 10r½ of the product is composed of fines (particles with diameters below 75μ) (c) The proportion of fines is related to the quantity of the polyvinylpyrrolidone used. (d) The proportion of fines is related to. the gas flow rate as the greatest amount of fines occurred at the highest flow rates and the 3™all«?st quantity o ":sre produced at the lowest flow rate. (e) The diameter "of the spray dried particles can be increased and the proportion of fines reduced by increasing the con increasing the spray angle and orifice diameter of the atomising nozzle, increasing the diameter of the chamber and minimising the gas flovr through the drier. (v) Friability : 0.6$ Samples of the spray dried products taken from the chamber fractions of the Experiment 1 were sieved to select microcapsules of diameter greater than 125u and these microcapsules" were then tested for friability in conventional manner by subjecting the microcapsules to stress and determining the quantities of particles produced of diameter less than 125u. The result shows that friability is low. The result of this test indicates that the microcapsules are sufficiently non-friable to resist substantial break up during blending, tablettin?, handling and the like . (vi) r'low Properties: The angle of repose (that is the maximum angle formed by a static heap of powder resting on a place horizontal surface to that surface) of the product of Example 1 is 28°. The angle of repose for the ampicillin trihydrate raw material was 64^.

This test indicates that the flow rate characteristics of the powders are improved. (vii) Bulk Densities: Bulk densities of the microencapsulated material are less than that of the raw material because of the large volumes of air trapped between the particles and the small volumes of air actually within the particles. The bulk density of. the product is 0.48 vrhilst that of the raw material in this case is 0.67. (vii) ■ Disintegration Time: . .

It was found that the coating agent shells dissolved on contact with the water to liberate the encapsulated powder as a uniformly dispersed suspension of particles of diameter less than 45μ· It was fouad that the disintegration time depended on the concentration of the polyvinylpyrrolidone and was 2 minutes in the case of Example 1.

Sxaisoles 2 and 3 Powders consisting of microcapsules of ampicillin trihydrate (995») coated with polyvinylpyrrolidone (ΐ?ΐ) were prepared by a method analogous" to that described in the previous Example except that the nozzle atomiser was replaced by a spinning disc atomiser. The moisture contents of these powders were determined by the Karl Fischer method0 The potency of the product was determined in conventional manner. The TQn of the products for Examples 2 and 3 was in all cases at. least that of the untreated raw material.

The results obtained were: Exacple Coating Inlet Outlet Koisture Potency IIo. Agent Temp. Temp. (°0 (°0 (5 (50 • 2 A 145 65 12.8 85 3 B 145 65 13.5 83 The potency of ampicillin trihydrate raw materials in products of Example 2 vras 86 and that of Example 3 was 835».

The results of Examples 2 and 3: h moisture ont nts of the sam l are ene al con X dried products can be controlled precisely and accurately.

The potencies of the ampicillin trihydrate samples within the microencapsulated products are not adversely affected by the spray drying process.

The accelerated shelf-life suitabilities of encapsulated poviders, · prepared from conventional raw materials are normally greater than those of the untreated raw materials.

The resistance to decomposition at high temperatures of spray dried powders prepared from ampicillin trihydrate wet cake, are- greater than those of the untreated raw materials produced by the conventional manufacturing method.

The shelf-life stability of ampicillin trihydrate in the spray dried form should be significantly improved.

EXAMPLE 4 (a) Formation of Slurry Amoxicillin trihydrate (33.3 kg) obtained from a wet cake of the material taken from a standard commercial production batch was added to a solution of polyvinylpyrrolidone (A) (0.242 kg); in demineralised water (40 kg) . The mixture was stirred during addition. Some foaming occurred during the continuing agitation but was reduced by the addition of a snail quantity of octano " (10 ml). The suspension was sieved through a 0.3 mm vibrating screen to remove clumps of β-lactam. antibiotic particles which, had not disintegrated during stirring. The sieving stage increased the foam present. The suspension was transferred to a feed tank where, (b) Tower Operation The suspension from the feed tank was pumped through a nozzle atomiser at about 25 kg/hr. The nozzle orifice diameter was set at 0.9 mm and the spray angle of the nozzle was set at 45°· A concurrent air flow was pumped through the spray drier at 850 kg/hr. and the temperature of the air adjusted to give an inlet temperature of 160°C and an outlet temperature of 65-67°C.

The product collected from the spray dryer after the internal separation of fines consisted of amoxicillin trihydrate encapsulated with 0.7 ^ of polyvinylpyrrolidone. The microcapsules were found to have an average dianeter of roughly 170μ.

Similarly, microcapsules of amoxicillin trihydrate could be prepared comprising 98.5^> amoxicillin trihydrate and 1.5» of polyvinylpyrrolidone A or 3.

Example 5 By using the process of Example 1, dustle&s, free-flowing powders consisting of microcapsules of ampicilli trihydrate in polyvinylpyrrolidone A were made with the following compositions s P-lactais antibiotic Polyvinylpyrrolidone A 98.0 2.0 98.5 1.5 99.0 1.0 99.2 0.8 99.25 0.7 2312 ^

Claims (1)

1. CLAIMS Ά powder comprising microcapsules having an average diameter of from 100μ to 300μ with at least of the microcapsules having diameters in the range 75μ to 450μ and which comprise to of aapicillin trihydrate or amoxycillin trihydrate coated by to of A powder as claimed in claim 1 wherein the microcapsules comprise to of ampicillin trihydrate or amoxycillin trihydrate and to of A powder as claimed in either claim 1 or claim 2 wherein at least of the microcapsules have diameters in the range 75μ to A as claimed in any one of claims wherein at least of the microcapsules have diameters in the range and A powder as claimed in claim 1 wherein the microcapsules comprise to of ampicillin trihydrate or amoxycillin trihydrate and to of polyvinylpyrrolidone which microcapsules have an average diameter between 150μ to having diameters between to 450μ and of which have diameters between 100μ to A process for the preparation of as claimed in claim which process comprises spray drying slurry comprising a suspension ampicillin trihydrate or amoxycillin trihydrate in a solution of vinylpyrrolidone in a A process as claimed in claim 6 wherein the slurry is dispersed into a drying cavity as droplets of diameter from 100μ to A process as claimed in 6 or 7 wherein the slurry contains of suspended A process as clained in claim 8 wherein the slurry contains of suspended A process as clained in any one of claims 6 9 wherein the contains to of polyvinylpyrrolidone on suspended A process as claimed in of 6 10 wherein the solvent is insufficientOCRQuality