(1985)
`
`73 - 77 73
`
`Ordered Mixing or Spontaneous Granulation?
`
`J. N. STANIFORTH
`
`(Received April 2,1985)
`
`SUMMARY
`
`Ordered mixes were produced using a
`fructose-based excipient as a coarse carrier
`component
`and
`fine-particle pyridoxine
`hydrochloride
`(vitamin B6) as the adherent
`component. Prior to mixing, the fructose
`agglomemtes were conditioned
`for 48 h at
`either 0% RH or 55% RH at 20 “C. Under
`these conditions, one lot of fructose had a
`moisture content of 0.24 wt.% and the other
`lot had a moisture content of 0.74 wt.%.
`mixing, thepowders were subjected
`to vibrution at various frequencies
`in the
`range 25 to 200 Hz and accelerations in the
`range 9.81 to 39.24 m/s2. It was found that
`whilst ordered mixes produced using fructose
`at 0.24 wt.% moisture content were unstable,
`those produced using 0.74 wt.% moisture
`content fructose were extremely stable and
`segregation resistant.
`The formation of ordered units with
`increased adhesion in carriers with higher
`moisture con tent suggested that these ordered
`mixes could be considered as spontaneous
`granulations.
`
`INTRODUCTION
`
`Hersey [l] first introduced the concept of
`ordered mixing to explain the behaviour of
`interacting particles
`in a powder. Fine
`particles adhere to other particles to form
`so-called ordered units. Some potential
`adhesive or cohesive forces responsible for
`the formation of ordered units or interparticle
`bonds were described by Hersey [l] and by
`others [2,3,4]
`London-van der Waals and
`other dipole forces; electrostatic or Coulomb
`forces; forces due to the presence of water
`such as surface tension forces and capillary
`suction potential
`forces; mechanical forces
`due to static frictional contact or interlocking
`
`of rough or re-entrant particle surfaces;
`chemical forces such as occur in chemisorp-
`tion or hydrogen bonding. The Table shows
`some examples of ordered mixing systems
`studied in which one of these interactions
`was considered to be the predominant force
`responsible for binding particles in ordered
`units.
`Comparison of this group of forces with a
`similar list produced for interparticle attractive
`forces in granules is, perhaps not surprisingly,
`very similar. The only significant difference
`between the list above and one compiled by
`Rumpf [9] for granules, is the absence of
`solid bridges as a class of forces responsible
`for formation of ordered units.
`
`TABLE
`
`of forces
`Some examples
`particles
`in ordered units
`
`responsible
`
`for binding
`
`Adhesion
`force
`
`London-van
`der Waals
`forces
`
`Electrostatic
`force
`
`Ordered unit
`
`Reference
`
`to contribute
`Considered
`to most ordered units
`
`Staniforth
`etal.
`[5]
`
`Coarse saccharide-based
`carrier particles and
`fine potassium
`chloride
`particles
`following
`tribo-
`electrification
`
`Staniforth
`and Rees
`
`Surface
`tensional or
`capillary
`forces
`
`crystals
`Coarse sucrose
`and fine salicylic acid
`particles mixed at three
`different humidities
`
`Mechanical
`forces
`
`Chemical
`forces
`
`Highly re-entrant, macro-
`porous
`lactose
`glucose
`carrier particles and fine
`potassium
`chloride
`particles
`
`No practical
`
`examples
`
`Stephenson
`and Thiel
`171
`
`Staniforth
`[B]
`
`0032-5910/85/$3.30
`
`@ Elsevier Sequoia/Printed
`
`in The Netherlands
`
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`Powder Technology, 45
`School of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY (U.K.)
`Following
`:
`or
`et al.
`

`

`74
`
`On the basis of this apparent similarity
`between granules and ordered units, there
`may be some justification for describing
`ordered mixing as a type of direct granulation.
`However, it is known that ordered units are
`prone to become destroyed during processing
`and, in general, particles in ordered units are
`far less strongly adhered than equivalent
`particles in granules.
`
`THEORY
`
`The force balance which exists at a given
`interparticle contact will be influenced by
`both particle properties and the particle
`environment. For example, it is likely that as
`particle diameter reduces below 100 pm, the
`van der Waals component of particle adhesion
`will become significant. In a low-humidity
`environment, contact or frictional electrifica-
`tion may lead to significant interparticle
`electrostatic forces, but at elevated humidities,
`the electrostatic component of particle
`adhesion will be less significant than forces
`due to the presence of adsorbed or condensed
`liquid layers.
`The theoretical contribution of London-
`van der Waals forces to the adhesion of a fine
`and a coarse particle in an ordered unit can be
`calculated. For a fine drug particle with a 45
`I.trn diameter resting on the surface of a coarse
`excipient particle having a diameter of 500 pm,
`the interparticle contact can be assumed to
`approximate to that for a sphere resting on a
`flat plate
`41:
`AR
`-
`r(:, = - 6H2
`where FA is the London-van der Waals force,
`A is the Hamaker constant, R is the radius of
`the sphere and H is the separation distance
`between particle surfaces, taken to be 4 X
`lo-” m, i.e., FA = 1 X lO-‘j N. However, the
`surface of the coarse excipient particle is
`porous and the drug particle can therefore
`be considered to be in extended contact with
`the carrier particle, so that
`AR
`A
`_
`6H2
`6nH3 lrpL
`
`or
`
`2AR
`FAE= -
`12H2
`
`where FAE is the London-van der Waals force
`for extended contact and p is the radius of
`interparticle contact.
`For a particle located on a slightly textured
`surface,p = 1 X 10-6m,i.e.,F,,=
`2.6 X 10P4N.
`This adhesion force is comparable with a
`value obtained experimentally for relatively
`smooth carrier particles, with slightly textured
`surfaces: 3.8 X lop4 N. Adhesion forces of
`this order were found to be characteristic of
`unstable ordered units [ 51.
`In cases where the pores or clefts in a
`carrier surface are too small to produce an
`increased van der Waals attraction, other
`means of enhancing the overall interparticle
`adhesion have been used. One method used
`to reduce disruption of ordered units by
`vibration of powder mixes was electrostatic
`charging which significantly reduced segrega-
`tion [6].
`Another method of improving interparticle
`adhesion is used in moist granulation and is
`due to adsorbed or condensed liquid layers
`on particle surfaces.
`Several equations have been derived to
`allow calculation of adhesion forces between
`particles due to surface tension and suction
`pressure in liquid films [lo, 111. These may
`be summarised using the following equation:
`
`F STSP = -@f(&
`
`6)
`
`where y is the surface tension of the liquid
`layer, D is the fine particle diameter and
`f(0, 6) is a function of 8 the contact angle and
`6 the bridge angle.
`Values for FsTsp for particles in the ordered
`unit described above vary between 2.33 X
`lop6 and 1.45 X lo-’ N, according to the
`method of calculation. Although these values
`are below those for van der Waals forces for
`fine particles adhered in clefts or pores, it is
`assumed that surface tension or suction
`potential forces will be responsible for (a)
`drawing particle surfaces closer together and
`(b) causing extended interparticle contact,
`and this will produce an increase in dispersion
`forces between the two particles.
`The aim of the present study was to
`investigate the effect of the presence of
`surface moisture on the stability of ordered
`units formed between a hygroscopic coarse
`excipient particle and a fine particle model
`drug.
`
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`[
`FAE= - + -
`

`

`Folkestone, U.K.). Frequencies were moni-
`tored using a frequency counter (Ferranti
`Electronics. Manchester, U.K.) attached to
`the output ‘of the conditioning amplifier.
`Accelerations were monitored using an
`accelerometer mounted on the horizontal
`base plate of the cylinder holder on the
`vibration table, as shown in Fig. 1. The
`output from the accelerometer was fed into
`signal conditioning amplifier and then to a
`vibration level monitor set to read R.M.S.
`accelerations.
`Following vibration under set conditions
`for 15 min, the homogeneity of the powder
`mix was re-determined using the sampling
`technique and spectrophotometric method
`described above.
`
`a
`
`Frequency Counter * Acceleration Monitor Vibration Table Frequency Generator 8 -F Power Amplifier Fig. 1. Schematic diagram of vibration model.
`
`75 MATERIALS AND METHODS
`Tabfine, type F94M (manufactured by
`Finnish Sugar Company, Espoo, Finland,
`supplied by Forum Chemicals, Reigate,
`Surrey, U.K.) is an agglomerated fructose-
`based direct compression tableting excipient
`and was used as the coarse carrier system.
`Fine-particle pyridoxine
`hydrochloride
`(vitamin Bb) was used as the adherent drug
`fraction at a concentration of 1 wt.%.
`Tabfine F94M was conditioned at two
`different humidities prior to mixing with
`pyridoxine hydrochloride powder. One lot of
`Tabfine F94M powder was dried to constant
`weight and stored at 0% RH in a desiccator
`containing fresh silica gel, for 48 h. A second
`lot of fructose-based Tabfine was allowed to
`equilibrate at a relative humidity of 55% at
`20 “C. The dried fructose agglomerates were
`found to have a moisture content of 0.24 wt.%,
`whereas the fructose agglomerates stored at
`55% RH had a moisture content of 0.74 wt.%.
`Ordered mixes containing Tabfine F94M
`and pyridoxine hydrochloride were produced
`by a two-stage process: initially, geometric
`mixing, or trituration, of the drug and
`excipient powders was carried out so as to
`ensure that the fine drug particles and agglom-
`erates of particles were broken up and
`uniformly dispersed throughout the excipient
`system. Secondly, the premixed powders
`were loaded into a cube blender (Erweka
`GmbH, Frankfurt, F.R.G.) and mixed for
`approximately 30 min. The homogeneity of
`the mixed powders was analysed by filling
`an interlocking stack of small Perspex
`cylinders with powder and removing samples
`at ten different levels. The samples were
`analysed for drug concentration by dissolving
`in volumetric flasks made up to 100 ml with
`distilled water and measuring the absorbance
`of the solutions at 290 nm using a U.V.
`spectrophotometer
`(Shimadzu Instruments,
`Kyoto, Japan). The standard deviation and
`coefficient of variation of the ten sample
`concentrations were determined.
`The interlocking cylinder stack was then
`reassembled and filled with the powder mix
`of known homogeneity. The stack was
`clamped in place on a vibration table (Fig. 1)
`and vibrations of known frequency and
`acceleration were applied using a vibration
`conditioning amplifier (Derritron Electronics,
`
`in moisture content
`The difference
`between the two lots of fructose-based Tabfine
`was only 0.5 wt.%, but the physical stability
`of the two powder mixes formed was very
`different. Ordered mixes containing the low
`moisture content Tabfine F94M were found
`to be extremely unstable when subjected to
`vibration under different conditions (Fig. 2).
`The segregation tendency of low moisture
`content mixes as characterised by the response
`surface shown in Fig. 2 ;vas typical of that for
`other ordered mixes where segregation occurs
`[12],
`maximal segregation occurred in
`conditions of low frequency and high accelera-
`tion. For these powder mixes, the segregation
`tendency was of a magnitude characteristic
`of that for unstable systems considered to
`behave like partially ordered random mixes.
`In contrast, mixtures containing the higher
`moisture content Tabfine F94M (0.74 wt.%)
`were found to be the most stable of any of
`the drug-excipient systems studied, there
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`RESULTS AND DISCUSSION
`i.e.,
`

`

`being no evidence of segregation under any of the test conditions (Fig. 3). This apparent difference in behaviour may be partly due to occlusion of the powder bed by the more cohesive Tabfine F94M with 0.74 wt.% moisture content, although even the lower moisture content sample immobilized large proportions of the powder under several different vibration conditions (Fig. 4).
`
`of variation
`coefficient
`between
`Fig. 2. Relationship
`and vibration
`frequency
`of spot samples drug content
`and acceleration
`for ordered mixes containing
`1 wt.%
`pyridoxine
`hydrochloride
`and Tabfine F94M with a
`moisture
`content of 0.24 wt.%.
`
`of variation
`between coefficient
`Fig. 3. Relationship
`of spot sample drug content
`and vibration
`frequency
`and acceleration
`for ordered mixes containing
`1 wt.%
`pyridoxine
`hydrochloride
`and Tabfine F94M with a
`moisture
`content of 0.47 wt.%.
`
`and
`frequency
`between vibration
`Fig. 4. Relationship
`acceleration
`and the percentage
`of the powder bed
`immobilized
`through
`changes
`in packing geometry
`for Tabfine F94M with moisture
`content of (a) 0.24
`wt.% and (b) 0.74 wt.%.
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`(a)
`

`

`It is considered to be more likely that the
`higher moisture content sample of Tabfine
`F94M held the increased mass of water as a
`surface film which was condensed at inter-
`particle contacts to form pendular bonds of
`the type commonly found in moist granules.
`The critical humidity above which water
`could be expected to condense to form a
`capillary system between particle contacts
`can be calculated
`[13].
`It is suggested [14]
`that below an RH of 65% capillary forces
`play no part in particle adhesion. However,
`according to the value taken for the B.E.T.
`coefficient for air-water or air-water saturated
`with fructose, the prediction of the point of
`condensation changes markedly. In addition,
`water exhibits special behaviour at surfaces,
`where polarity has a marked influence on
`adsorption because of the ability of the water
`molecule to form H+ bonds and water may
`undergo chemisorption as well as physisorp-
`tion [ 151. Water may also be associated non-
`stoichiometrically within the fructose lattice
`and it might be expected that although most
`of the water would be present as a thin
`adsorbed film at 55% RH, there may be at
`least some parts of the particle surface where
`capillary condensation
`could occur and
`contribute to particle bonding.
`In either case, the striking result of the
`presence of elevated surface moisture levels
`appears to be a spontaneous granulation of
`drug and excipient particles through forma-
`tion of extremely stable ordered units.
`
`CONCLUSION
`
`The stability of ordered mixes formed
`between
`fine pyridoxine hydrochloride
`particles and coarse fructose agglomerates was
`
`sensitive to the
`found to be extremely
`moisture content of carrier particles.
`Low moisture content carrier particles
`formed unstable ordered mixes, whereas at a
`slightly higher moisture content, the fructose
`agglomerates formed ordered mixes which
`were extremely stable.
`The segregation resistance of these fructose
`systems and the.apparent role of moisture in
`formation of strong ordered units suggested
`that ordered mixing could be considered to be
`a spontaneous or direct granulation.
`
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`
`J. A. Hersey,
`M. C. Coelho and N. Harnby,
`(1978) 20i.
`Powder Technol., 20
`J. A. Cross and A. Cetronio,
`
`c
`
`(1975) 41.
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`77
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`