TTablet production is an essential operation for thepharmaceutical industry, considering the majority ofdrugs are being delivered in this form. Tablet pressesoperating on the principle of direct compression havebeen developed over several decades and it is nowpossible to make in excess of one million tablets perhour. Developing formulations that process well inthese units to consistently deliver uniform tablets withthe required properties, remains an ongoing chal-lenge.

The Challenges Posed By TablettingWith direct compression, tablet ingredients are fed toa press as a blended powder. The blend contains var-ious components — filler, inert carrier, active pharma-ceutical ingredient (API), and lubricant — each ofwhich fulfils a different function in terms of tablet orprocessing performance. Wet or dry granulationprocesses may be used to improve the flowability ofthe blend.

Tablet quality is quantified in terms of strength,weight, dimensions, and API content, the requiredproperties being produced through control of theflowability and compressibility of the mix. This isachieved by manipulating variables such as particlesize and shape, surface texture, and water content, andby addressing fundamental issues such as excipientchoice and the concentration of each component inthe final formulation. Quality may be highly depen-dent on processing speed so productivity may beadversely affected if flow properties are not optimal.

The aim is to develop a formulation that flows eas-ily into the die, releasing air to form a strong tabletduring compression. Segregation must be avoided toensure uniform tablet composition. These goalsrequire careful optimization of the properties of theblend. For example, small particles with high surfaceroughness tend to produce strong tablets. While this isan advantage, they may not flow well within the press.

Fundamental correlations between particle proper-ties and tabletting performance remain elusivebecause of the complexity of powder behavior1. As aresult, researchers still tend to rely to some extent onart and experience when developing a completely

new tabletting process, or predicting the likely behav-ior of a new formulation in an existing press.Compaction simulators are also used, to assess howformulations will perform under different tablettingconditions. Tools that can provide information at anearlier stage, simply through analysis of a material, areobviously a cost-effective, time-saving alternative; thepowder rheometer is one such tool.

Powder Rheometer MeasurementsA unique feature of powder rheometers is dynamiccharacterization, measurement of a powder in motion.The energy required to induce or to maintain a partic-ular flow pattern is determined from measurements offorce and torque, recorded as a blade rotates throughthe sample at a certain speed. A conditioning stepbefore analysis ensures that the initial packing state ofthe material, and hence the measurement, is repro-ducible. This single traverse of the blade up and downthrough the sample produces a loosely packed bed,the gentle slicing and lifting action allowing the parti-cles to come to rest in a homogenously packed state.

The baseline energy measurement recorded for aconditioned bed, is highly differentiating and, there-fore, valuable in its own right for assessing differencesbetween samples (QC applications). For example,pharmaceutical manufacturers have found that with apowder rheometer they can differentiate betweenbatches of material of the same grade. This permits theselection of those with the preferred flow properties,without changing the validated formulation.

In combination with other experiments, this base-line measure can also be used to systematically inves-tigate the impact on flow properties of variables suchas consolidation, aeration, moisture content, flow rate,and composition. Modern powder rheometers nowalso measure shear and bulk properties, which can becorrelated to different stages of the process.Permeability measurements, for example, indicate theability of a powder to aerate and de-aerate, while com-pressibility data is relevant to processing steps wherethe powder is consolidated. Cohesivity, measured byshear testing, provides insight into a powder’s abilityto flow from a static storage condition and also its

Formulation Optimization For Tabletting Applications

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By Reg Freeman,Managing Director,Freeman Technology

capacity to stick together in tablet form. Wall frictiontests indicate the likelihood of the material adheringto the die walls in the tablet press.

For tabletting, segregation, de-aeration, andflowability characteristics are particularly important.The following case studies show how powderrheometry can be used to investigate these aspectsof behavior.

SegregationSegregation of a blend can lead directly to inconsis-tencies in tablet composition and rejection of a com-plete batch of product on the grounds of unevenAPI distribution. Furthermore, segregation of a lubri-cant can be detrimental to powder flow, and ulti-mately to tablet strength. If lubricant is poorly dis-tributed within a tablet then capping can occurwhere the tablet splits or shears along the layer oflubricant that has formed within it. The mechanisms of segregation are fairly well

understood and are related to specific material prop-erties. Particle size and distribution, theease with which the material flows(segregation is less of a problem withcohesive powders), and the way inwhich the material behaves when aer-ated, are all important factors2.Data collected during a test designed

to investigate segregation are shown inFigure 1. Repeat measurements of flowenergy are made using the standardtest cycle. Each measurement is pre-ceded by five segregation cyclesinvolving rotation of the blade oncethrough the sample in a three-dimen-sional, low-stress flow pattern,designed to promote segregation. Thehighly repeatable nature of the blade’smovement during the segregation cycleallows easy comparison of the vulnera-bility of different blends. Observedchanges are due to segregation and notattrition. The results show successive increases

in flow energy consistent with ongoingsegregation of the sample. In theabsence of segregation the measuredflow energy would be constant. Thefinal data point on the graph was mea-sured after the sample had beenreturned to its initial state, by tumblingand mixing to homogenize. It providesconfirmatory evidence that theobserved changes are due to segrega-tion.Repeatedly carrying out the basic flow

energy measurement (referred to as

stability testing), or making measurements asdescribed above, are both effective and practicalways of assessing the propensity of a sample to seg-regate. These data can be used to directly determinethe likelihood of an associated problem occurringduring processing.

Air ReleaseIf air is compressed in the die with the blend, ratherthan being released prior to or during compression,when pressure is removed the air will expand, rup-turing the tablet3. A blend that releases air relativelyeasily is therefore preferable in order to avoid lami-nation or splitting; materials that retain air are muchmore likely to result in catastrophic tablet failure.Powders pick up and release air at different rates,some aerating easily and releasing entrained airrapidly, others behaving very differently. The ease with which a powder is aerated can be

quantified by measuring flow energy as air flowsthrough the sample. The ability of a material to

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FFiigguurree 11:: Flowability energy as a function of segregation for a coarselymilled lactose which had previously been subjected to attrition to producefines

FFiigguurree 22:: De-aeration of three different lactose materials

release air (de-aerate) can also be determined by car-rying out successive measurements once the air hasbeen switched off. Powder rheometers uniquely allowmeasurement of materials in an aerated state and aretherefore especially valuable for investigating thisaspect of behavior. Figure 2 shows de-aeration data forthree different lactose materials.It is evident from the data that spherical, spray-dried

lactose de-aerates readily, achieving 100% recovery toBFE in just three de-aeration cycles. The comparablysized coarsely milled lactose also de-aerates readily,but does not fully return to its baseline state until thefifth cycle. The finely-milled lactose, on the other hand,releases air much less easily — the cohesive nature ofthe fine particles encouraging entrainment.Interestingly, the materials show a similar degree ofrecovery when the air is simply turned off (n=0), yetwhen the powder is disturbed mechanically, the prop-erties are quite different. Results from tests such as these, correlate directly

with the likelihood of producing tablets that will failcatastrophically following compression as a result ofair release. They rapidly identify potential problemswith a new formulation.

FlowabilityPoorly flowing blends can result in improper filling ofthe tablet die, leading to inconsistencies in tabletweight. Materials vary in terms of their flowability andconsequently their optimum processing rate; formula-tion and processing speed therefore need to be care-fully matched for each application. Poor flow proper-ties, resulting from the use of cohesive materials forexample, may also result in flow stoppages, and anunacceptable amount of downtime.Additives are often used to improve the flow proper-

ties of a tablet formulation. A common example fromthe pharmaceutical industry is magnesium stearate,which in addition to improving flow behavior, pro-vides lubrication between the die and the tablet, so

that less ejection force is needed. The impact of thisadditive on flow energy can be observed from Figure3, which shows measurements for a range of lac-tose/magnesium stearate blends.These data show that while 0.1% magnesium stearate

provides some improvement in flow behavior, theoptimum dosing level lies between 0.15 and 0.20%.Concentrations above this level yield no furtherenhancement in flow properties. High concentrationsare more likely to cause segregation problems and, asdiscussed earlier, increase the likelihood of capping, sothis information is extremely useful.

ConclusionOptimizing a formulation for an existing or new tablet-ting process requires careful consideration of the fac-tors affecting processability. Powder rheometry is anexcellent option for such investigations, providinginformation that directly correlates with processingbehavior. It allows researchers to predict the likely per-formance of a formulation at an early stage, yieldingvaluable data for process design and optimization.Particularly critical is the ability of such devices todynamically characterize powders in aerated, condi-tioned, and consolidated states.By matching the critical flow properties of new for-

mulations with those known to process well in a spe-cific press, or by understanding the likely impact of dif-ferences between formulations, researchers are moreable to develop effective tabletting processes. This hasa direct impact on product quality and on productivi-ty. Such process relevance, which is far from unique totabletting, explains why powder rheometry, although arelatively new analytical technique, is increasinglywidely used by those who recognize its potential toprovide new insight into powder behavior.

About The AuthorsReg Freeman is founder and managing director ofFreeman Technology. He is a mechanical engineer

with extensive experience in designingtesting systems for evaluating the physicalproperties of liquids and solids, and inthe mid 1990s conceived an innovativeapproach to powder testing that is nowpatented worldwide.

References1. “The future of compaction” B.A.C

Carlin Pharmaceutical Technology. June2004.

2. “Maintaining product uniformityand uninterrupted flow to direct compres-sion tableting presses” J. Prescott andR.Hossfeld Pharmaceutical Technology 18(6), 1994 p99-114.

3. “A day in the life of a tablet” T. LewisPMPS Spring 2002. ●

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FFiigguurree 33:: Flow energy measurements for different blends of lactose andmagnesium stearate