Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Carboxymethylstarches in Wet Granulation

Abstract

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

A Process to Produce Effervescent Tablets: Fluidized Bed Dryer Melt Granulation

The purpose of the present study was to apply melt granulation in a fluidized bed dryer (fluidized bed dryer melt granulation) to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium bicarbonate to make tablets. This study permitted us to establish that such process parameters as concentrations of polyethylene glycol (PEG) 6000, residence times in the fluidized bed dryer, fineness of PEG6000, fineness of initial mixture effervescent systems, and efficiency of two lubricants markedly affect some granule and tablet characteristics. It is a dry process that is simple, rapid, effective, economical, reproducible, and particularly adapted to produce effervescent granules that are easily compressed into effervescent tablets.     

Granulation Rheology I: Equipment Design and Preliminary Testing

One of the most common pharmaceutical dosage forms is the compressed tablet, and of the several methods of preparing tablets, wet granulation remains widely used throughout the pharmaceutical industry. An apparatus was designed to follow the physical changes occurring in the granulation process. Its operation and preliminary results are presented.

As dry solid is wetted with granulating liquid, it passes through several stages, as it becomes wetter, it should exhibit a resistance to flow analagous to a viscous liquid. This resistance (force) can be measured. The test procedure follows the material from a dry powder through its maximum resistance and finally to a slurry. Such profiles could represent a characterization method for the solid and/or the liquid.

Materials tested included six common tablet excipients; these have been limited to single component granulations. Results indicate this apparatus is reproducible for these simple systems. Materials are shown to behave differently in the granulation process, and the apparatus appears capable of distinguishing between different materials.     

Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets

During the development of a tablet formulation of a cohesive, fluffy investigational drug, a novel moisture-activated dry granulation (MADG) process was studied in comparison with two conventional granulation methods, i.e., wet granulation and dry granulation with a roller compactor, as well as with a direct compression formulation method. The MADG method produced granules with excellent flowability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. The tablets prepared using the MADG method had better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Melt Granulation in A Laboratory Scale High Shear Mixer

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Melt Granulation in A Laboratory Scale High Shear Mixer

Abstract

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

The Control of Drug Release from Conventional Melt Granulation Matrices

Abstract

Sustained release potassium chloride tablets were prepared using a melt granulation formulation in a Baker Perkins Granulator. Parts of the validation for this manufacturing process are highlighted in this paper including granulation end point temperature, incorporation of extragranular excipients, amount of wax in the formulation, granule cooling rate and scale of the operation. A number of other factors have been studied which are not Included here although they are no less important. The release of potassium chloride from tablets was found to be dependent on the wax level and the amount of extragranular excipients (“wicklng agent”). Within the controlled production process, any variation in granulation end point temperature and granule cooling rate should not have any significant effect.     

Granulation of Pharmaceutical Powders by Compaction an Experimental Study

Among technological which improve properties of powder before tabletting, dry granulation has been studied with a new compactor-granulator. An experimental study was carried out to understand the influence on powders of the adjustment of speeds and pressure during roll-compaction. The results obtained on an active substance are detailed in this article.     

Granulation of ibuprofen/isonicotinamide co-crystals by continuous spray granulator (CTS-SGR)

The importance of granulation is paramount for tablet manufacturing, and is based on the fact that granulated powders are characterized by improved flowability, compressibility, segregation, and dust reduction. The aim of this study was to prepare and characterize continuous granules of high drug content by using a continuous-spray granulator (CTS-SGR). Ibuprofen (IBU), a drug of low-flowability, was selected as the model drug. As IBU has a low melting point and cannot easily granulate on its own, we employed isonicotinamide (INA) as a coformer that would allow us to prepare co-crystal granules containing 60 % IBU. The results of the undertaken differential scanning calorimetry and powder X-ray diffraction revealed that the IBU and the INA in the granules formed co-crystals. The granulation conditions affected the particle size and the yield of the granules; in fact, a low air supply temperature, a low atomizing air rate, and a high solution flow rate ensured a high granulation efficiency. Moreover, continuous granulation increased the yields of the formulations compared to those obtained through a short-run granulation, and high yields were obtained after applying a low atomizing air rate. The circularity of the granules exceeded 90 %, and their flowability improved when compared to that of the IBU bulk. The undertaking of dissolution studies revealed no change in the elution amount of IBU as a result of the co-crystallization. Our study shows that it is possible to produce high-content IBU granules in a direct and continuous manner through the co-crystallization of IBU and the use of a CTS-SGR.     

Evaluation of the Granulation of a Hydrophilic Matrix Sustained Release Tablet

Wet granulation of a hydrophilic sustained release matrix tablet formulation has been studied. A fractional factorial experimental design was employed to identify principal influences and interacting factors from the following : granulation fluid volume, mixing time, mixer speed and inclusion of a wet screening step. Fluid volume and mixing time were primary factors affecting mean granule size. Fines in the granulation were reduced at higher fluid levels and by inclusion of a wet screening operation. There were several interacting factors influencing the particle size properties of the granulation. The factors studied had little influence on the bulk density of the granulation.

The influence of granule mean particle size on flow, compressibility and drug release from finished tablets was evaluated. Flow and compressibility were influenced by granule properties and the data generated suggested that should final tablet properties deteriorate on scale up it may be possible to ameliorate the effect by modification of granulation fluid volume or mixing time or both.

The factors studies had no influence on release of drug from finished tablets.     

Granulation of ferrosilicon alloy by rotary multi-nozzles cup atomizer: Granulation behavior and model formation

Nowadays, ferroalloys are mainly produced by mold casting and crushing process in China which have obvious drawbacks like low efficiency and high energy consumption. In the present study, a novel process which was based on a rotary multi-nozzles cup atomizer (RMCA) was suggested on FeSi75 (alloy containing 75?wt.% Si). A circle of water curtain was set around the rotary multi-nozzles cup atomizer. According to the calculation results of atomization mechanism, the granulation process agreed with Rayleigh’s mechanism. During the breakup of the alloy ligament, the surface tension plays an important role on the formation of droplet, and the effect of centrifugal force on the diameter of the alloy droplets becomes obvious with the increasing of the rotating speed. In the current study, the models of the traveling trajectories and the heat transfer of the alloy droplet are established. It is found that the solidification time of droplet with different thickness of solidification layer increase with the increase the alloy droplets’ diameter. And the thickness of water curtain required for cooling the alloy increases with increasing the rotating speed.     

Preparation of Essential Oils Loaded Granule by Melt Granulation

Abstract

A comparative study on three granulation methods; melt granulation, fluidized bed granulation and wet granulation was performed to fabricate an essential oils loaded granule. The granule properties such as particle size distribution and the loading efficiency of anethole from fennel and cinnamaldehyde from cinnamon showed that the melt granulation in a high shear mixer was the most feasible method among the three methods.

In melt granulation, the granule particle size was well controlled by polyethylene glycol 6000 (PEG) content of which the optimum value was found to De 20%. Impeller speed and massing time in high shear mixer had small contribution to the particle growth when PEG content was optimized, while PEG particle size had some effect. Finer PEG powder improved the uniformity of granule size. Moreover, the cooling method of the hot mass affected the final granule properties significantly. The cooling with a fluid bed dryer was the best method.

Both of the retention rates of anethole and cinnamaldehyde in the final granule were more than 95% of initial doses irrespective of cooling method. Further, the adoption of a fluid bed dryer enabled very rapid cooling of hot granule with negligible loss of essential oils.     

Comparison of microstructure and solidification behavior of rapid quenching with bulk undercooled superalloy

Microstructure and solidification behavior in rapid quenching (i.e., gas-atomized powders and melt-spun ribbons) of superalloy have been compared with bulk undercooled superalloy. The application of a molten salt denucleating technique combined with thermal cycle enables such investigation over a wide range of undercooling up to 210 K. The microstructure formation has been discussed for both methods of solidification with respect to undercooling, nucleation, and recalescence as well as recrystallization during post-recalescence. Comparison of the observed microstructure and morphologies indicates that the melt-spun ribbons and the gas-atomized powders with cooling rate above 10⁴K sec^–1crystallize only after achieving a large degree of undercooling, which becomes higher and higher with the increase of cooling rate. Furthermore, it should be noted that, grain refinements, which play a decisive role in the undercooled as-solidified structure, however, result from different sources in the rapid quenching process.     

The Effect of the Wet Granulation Process on Drug Dissolution

Abstract

Wet granulation can be an important processing step for pharmaceutical solid dosage forms. In this investigation emphasis was directed towards the influence of a “simple” wet granulation process on drug release from granules and their resulting tablets. Direct compression blends of the same materials were used as controls. Binary mixtures containing a 5% level of either theophylline, hydrochlorothiazide or chlorpheniramine maleate in microcrystalline cellulose or lactose were granulated with water. Experimentally, the powders were dry blended in a planetary mixer, wet granulated, and subsequently wet milled and dried. No dry milling step was included. Granule characterization consisted of particle size, density, porosity, compression and dissolution testing. Dissolution results varied with the drug, as expected, and dissolution at 10 minutes ranged from 35 to 95 % release. In general, however, the results indicate that dissolution from granules and the corresponding direct compression blend are similar. Although differences in compressibility were observed in the systems studied, granulation was not found to be detrimental to drug release.     

Polymorphic Changes of Thiamine Hydrochloride During Granulation and Tableting

Thiamine hydrochloride was granulated using an instrumented fluidized bed granulator (Hüttlin HKC 05-TJ). Granules consisting of pure thiamine hydrochloride were produced using an aqueous solution of thiamine hydrochloride as the granulating liquid. The effects of process variables such as inlet air temperature, spray rate, and amount of granulating liquid on granule properties are described. Particle size distributions of granules depended mainly on the amount of granulating liquid sprayed into the powder bed. Granules were tableted on a rotary tablet press at four different compression forces. Crushing strengths and disintegration times of all tablets were found to be very low after manufacture, but increased considerably after 4 months of storage at room temperature. Granular materials showed “caking” under the same storage conditions. These changes could be attributed to alterations of the polymorphic form of thiamine hydrochloride. The water-free form, being present directly after granulation, absorbs humidity very fast and is transformed into the monohydrate, which is stable at room temperature. Loss of water takes place during the drying phase of the granulation process and on storage of the substance at temperatures of 50°C and 80°C. During storage at room temperature while exposed to humidity, a transformation into the hemihydrate was observed. This polymorph is transformed during thermal analysis at about 190°C to a water-free form that is stable at higher temperatures.     

Tableting Properties of Experimental and Commercially Available Lactose Granulations for Direct Compression

Abstract

Lactose granulations (125-250 μm) were prepared from two different β-lactose monohydrate powders and one roller dried B-lactose powder respectively, by wet granulation with only water as a binder. As an effect of the granulation process, the flow properties improved, but the compactibility decreased. Moreover, the lubricant sensitivity of the granule fractions was higher than found for the starting materials. The compactibility of the granule fractions was found to be dependent on the type of lactose, the surface area of the starting powder and the granule bulk density. For lubricated lactose granulations, the lubricant sensitivity, expressed as Lubricant Sensitivity Ratio (LSR), increased with an increase of bulk density. The β-lactose content of roller-dried β-lactose is hardly affected by the granulation process, which explains the good compactibility of the granule fractions prepared from this type of lactose. On the other hand, anhydrous α-lactose present in the roller-dried β-lactose starting material is converted into α-lactose monohydrate during the granulation process, which improves tablet disintegration.

The compaction properties of commercially available lactose granulations have been compared with those of the experimental granulations and with a free flowing sieved α-lactose monohydrate. As an effect of the higher powder surface area and the relatively low bulk density, Tablettose^R has a better compactibility than α-lactose monohydrate 100 Mesh. The excellent compactibility of another commercially available lactose granulation, Pharmatose^K DCL 15, was attributed to the presence of more β-lactose, providing strong intergra-nular cohesion.