WHITEPAPER

The Definitive Guide to Physical Characterization for Pharmaceutical Solid Dosage forms

The majority of pharmaceutical products are delivered in solid dosage form, as tablets, capsules, granules and powders. Quality by Design (QbD) calls for rigorous identification of the Critical Quality Attributes (CQAs) of pharmaceutical products, the properties that define clinical efficacy, and of the Critical Material Attributes (CMAs) that impact them. For solid dosage forms, such characteristics often include physical properties of the drug formulation such as particle size or of the finished product, the porosity of a tablet, for example, which can directly impact disintegration and dissolution behavior. More broadly, a strong set of fundamental physical measurements provides a secure foundation for understanding the science of a given formulation and for demonstrating understanding to a regulator, facilitating the submission process.

In this whitepaper we examine the physical analytical techniques that support the development of safe, efficacious solid dosage pharmaceuticals. Focusing on parameters that are often CMAs and/or that are particularly helpful in elucidating formulation and process behavior we discuss the strengths and limitations of alternative measurement techniques and application of the resulting data.

The attractions of solid dosage formsTablets are the most common solid dosage form, and more broadly, the most widely used vehicle for drug delivery. Inexpensive and relatively easy to manufacture, package and transport, tablets enable accurate dosing, offer good chemical and physical stability and enjoy a high degree of patient acceptance. Coatings can be applied to ease swallowing, mask unpleasant tasting ingredients and/or enhance stability. With advanced tableting technology it is possible to exert considerable control over the rate at which the drug delivered, from controlled released products that ensure steady blood concentration profiles over prolonged periods to orally disintegrating tablets (ODTs) that disintegrate rapidly to offer faster action than more conventional tablets. ODTs are also particularly useful for patients suffering from dysphagia (difficulty in swallowing) and can be taken without water which can be advantageous in certain clinical settings.

Tablet formulations consist of one or more active pharmaceutical ingredient (APIs) blended with a range of excipients including fillers, binders, lubricants and disintegrants. Granulation, wet or dry (compaction), is a routine precursor to tableting that simultaneously stabilizes API distribution, thereby safeguarding content uniformity, and improves processability. Granules may be engineered to exhibit enhanced flow characteristics, relative to the original blend, and an improved response to compaction. Reducing the risk of adherence to processing equipment may be an important issue for ODT formulations, which are often manufactured under low compaction pressures, though lyophilization (freeze-drying) is an also a widely adopted processing route.

Beyond tablets lies a wide range of alternative solid dosage forms that deliver benefits for specific types of formulations, for the treatment of certain illnesses, and/or for discrete patient groups. These include [1,2]:

• Dry powder inhalers (DPIs) – DPIs deliver API(s) directly to the the lung, primarily for the treatment of pulmonary disease though the ability to by-pass the gastrointestinal tract can be an advantage for the delivery of systemic drugs susceptible to digestion.

• Hot and cold instant drink preparations – powders or granules that dissolve rapidly in water to form a palatable drink, as exemplified by cold and flu remedies, combine high patient acceptability with the potential for rapid API release since the drug dissolves completely before entering the body. The swallowing difficulties associated with tablets are eliminated.

• Capsules – these can be easier to swallow than tablets and are particularly advantageous for formulating APIs with an unpleasant taste or odor.

• Effervescent tablets – though sold in tablet form these are usually designed to be dissolved in water to form a drink in the same way as powder/granules and offer similar benefits.

Micromeritics Instrument Corp.

WHITEPAPER

2 of 14

The API dissolves completely before entering the body, offering potential for enhanced bioavailability, especially for those with impaired gastric function, and high API loading.The API dissolves completely before entering the body, offering potential for enhanced bioavailability, especially for those with impaired gastric function, and high API loading.

• Orally disintegrating granules – supplied in pre-dosed ‘stick packs’ these fine granules dissolve rapidly in the mouth without any additional liquid, in an analogous way to ODTs, and are particularly useful for patients minimizing fluid intake such as those on dialysis.

• Powders for reconstitution – as exemplified by lyophilized formulations. Lyophilization extends the shelf life of biopharmaceutical formulations via the removal of water producing a ‘cake’ that must be completely re-dissolved to recreate a dose with controlled properties for injection or infusion within the clinical setting.

For all these forms, clinical efficacy relies on dissolution and absorption of the API, via circulation into the bloodstream unless the drug is locally acting. A primary focus of physical characterization is therefore the elucidation of dissolution, and where relevant, disintegration behavior. Understanding and controlling parameters such as particle size, surface area, porosity and flowability that impact these characteristics by influencing the structure and properties of the finished product is vital.

Working in a QbD environmentOver the last decade or so QbD has progressively shaped working practice within the pharmaceutical industry. The defining principle of QbD as noted in ICHQ8 [3] is that ‘quality cannot be tested into products, i.e., quality should be built in by design.’ QbD is a systematic, risk-based approach, that calls for the development of a rigorous understanding of the product and the manufacturing process through the application of sound science. It has a direct impact on the experimental studies carried out, the analytical techniques required and their application.

A Quality Target Product Profile (QTPP) defines how the product will deliver the quality, safety and efficacy required. For a tablet, a QTPP might therefore specify dosage strength and tablet design (scoring, coating, modified release etc.), information about the pharmacokinetic profile – how

fast the drug concentration will peak in the bloodstream, and include a stability specification defining how long the product can be safely stored before performance is impaired. CQAs are parameters that must lie within a certain range to ensure that the QTPP is met. So, dosage strength is safeguarded by controlling dose uniformity, which is typically a CQA for tablets, as is dissolution profile because of its impact on API release rate into the bloodstream [4].

A focus of experimental studies is to identify the properties of raw ingredients that together with certain process parameters control the CQAs; these are the CMAs and Critical Process Parameters (CPPs) respectively. The aim is to establish a design space, a set of specifications/manufacturing controls that define an envelope in which product of acceptable quality can be made consistently and reliably. Of course, the design space is unique for each product, not just in terms of the actual specifications, but with respect to the parameters identified as CMAs/CPPs. For example, depending on the characteristics of the formulation and the process the particle size of the API may be a CMA/CQA because of its impact on segregation and by extension dose uniformity, or dissolution profile.

This brief overview of the application of QbD illustrates the rigorous understanding of product and process behavior that it demands, a much greater understanding than was traditionally developed to support a new drug submission. QbD is directly associated with increased effort and information gathering at the R&D stage but offers considerable reward in return. Process changes within the design space are not subject to further regulatory approval, so the incentive for robust definition is considerable. Furthermore, submissions demonstrating a higher level of formulation and process understanding represent a lower risk and are therefore subject to a more flexible regulatory approach. Greater knowledge also reduces the risk of operational failure, and offers enhanced flexibility for example, for supply chain optimization. Optimization of the analytical toolkit has an important role to play in boosting the effectiveness of information gathering and reducing the effort and investment needed to access these gains.

In the following sections we look at the physical characteristics that can be useful in developing a robust and secure ‘fingerprint’ of a solid dosage form and the techniques that can be used to measure them. These properties provide a secure foundation for the elucidation of product performance, supporting efficient product development and, as the product transitions into commercial production, effective troubleshooting, quality control, and counterfeit detection.

WHITEPAPER

3 of 14

Particle sizeMotivation for measurement

Particle size routinely forms part of the specification for an API, and indeed for an excipient, because of the multiple impacts that that it can have on product performance and processability. These are summarized in ICHQ6A [5] which presents a decision tree for setting acceptance criteria for a drug substance particle size distribution, highlighting that particle size can impact:

• Dissolution, solubility or bioavailability

• Processability of the formulation

• Drug product stability

• Content uniformity

• The appearance of the finished product

For a solid dosage formulation, finer particles are associated with faster dissolution. Rapid and complete dissolution is essential for formulations administered in solution form and has the potential to accelerate drug uptake in vivo. For inhaled drugs, a fine particle size distribution is essential since the upper size limit for penetration to the lung is known to be around 5 µm.

However, a finer particle size, or the presence of fines, often leads to an increase in cohesivity within the formulation, which can impact important processing characteristics such as flowability and compressibility. Particle size distribution influences compaction behavior, with higher levels of fines associated with regularly encountered tablet quality issues such as capping. Furthermore, the particle size distribution of raw ingredients directly impacts the ease with which they blend, and conversely, segregate (see below).

Making measurements

Particle sizing techniques well-suited to pharmaceutical applications include the Electrical Sensing Zone technique or Coulter Principle and static light scattering, otherwise known as laser diffraction.

The Electrical Sensing Zone technique determines particle size on the basis of the change in electrical resistance caused by liquid displacement as a particle passes through an orifice (see figure 1). The particle size reported is the equivalent spherical Electrical Sensing Zone diameter or Coulter diameter, the diameter of a sphere of the same material that gives the same change in electrical resistance as that of the measured particle. The measurement range runs from ~0.5 to 250 µm.

The Electrical Sensing Zone technique is fast and provides real-time particle size distribution data of high resolution. Particles are sized one-by-one, generating particle count and concentration data, alongside size metrics, that can be particularly useful in dissolution studies. Reported particle size distributions are number-based making them highly sensitive to both fines and over-sized particles. A key feature is that measurements are essentially unaffected by the physical properties of the sample, with the exception of accessible porosity, enabling the measurement of blends containing particles with mixed or varying properties.

0

R

R

t

t

t

R

Figure 1: Particles passing through the orifice of an electrical sensing zone instrument displace fluid triggering an electrical pulse that correlates with particle size.

Reflected ray

Refracted ray

Diffracted ray

No interaction - undeviated ray

Transmitted afterinternal reflection

Transmitted ray

Figure 2: Static light scattering determines particle size from measurements of the scattering pattern produced as light interacts with the sample.

WHITEPAPER

4 of 14

A static light scattering analyzer determines particle size distribution on the basis of the light scattering pattern produced by the sample; measurement range extends from ~40 nm to 2500µm (range quoted is for Micromeritics Saturn DigiSizer® II). The particle size reported is the spherical scattering diameter or Mie diameter, the diameter of a sphere of the same material that produces a scattering pattern that best fits the observed pattern.

Static light scattering is a fast, well-established technique with a very broad dynamic range. Instruments configured with a charge coupled device (CCD) for scattering detection significantly boost resolution of the technique, particularly at the extremes of the particle size distribution, substantially enhancing sensitivity for the quantification of fines and coarse material. Such systems are highly differentiating and can be particularly valuable for rationalizing the performance of closely similar samples.

Particle ShapeMotivation for measurement

Various aspects of particle behavior are governed not just by size but also by particle shape, a parameter that has historically been difficult to investigate, with manual microscopy traditionally deployed for such studies. Along with particle size, particle shape directly influences dissolution profile and bioavailability, formulation flowability and compressibility characteristics. For example, more regular shaped particles will generally exhibit better flow properties than irregular shaped ones of equivalent size.

Particle shape data often prove useful for troubleshooting, either a product, a process or an analytical method. Particle sizing methods typically provide minimal or no differentiation between particle populations in a blend whereas particle shape can, for example, reveal the presence of a very small population of contaminating particles of very different shape to the bulk. Changes in shape can help to rationalize changes in process behavior stemming from altered flowability or anomalies in the particle size distribution data reported by techniques influenced by shape such as static light scattering.

Making measurements

Dynamic image analysis quantifies particle shape, and size, from images of individual particles produced by transmitting light through a sample of suspended particles flowing through a thin flow cell (see figure 3). Images are recorded at a rate of thousands per second to generate statistically significant data in just a few minutes. Selection of an appropriate particle model extracts relevant descriptors of particle shape for

the specific sample. These can include parameters such as circularity, form factor, compactness, convexity, fiber length, width and aspect ratio, and smoothness (see figure 4/Table 1).

Dynamic image analysis quantifies particle shape, and size, from images of individual particles produced by transmitting light through a sample of suspended particles flowing through a thin flow cell (see figure 3). Images are recorded at a rate of thousands per second to generate statistically significant data in just a few minutes. Selection of an appropriate particle model extracts relevant descriptors of particle shape for the specific sample. These can include parameters such as circularity, form factor, compactness, convexity, fiber length, width and aspect ratio, and smoothness (see figure 4/Table 1).

Figure 3: Dynamic image analysis captures 2D images of individual particles.

Circle model

ECAD ECPD BCD

Ellipse model Fiber model

L W

Irregular model Polygon model

L

W

Rectangle model

Wasp

L

LW

Model Descriptors Reported

Circle Heywood diameter, equivalent perimeter diameter, bounding circle diameter, circularity, form factor, compactness.

Ellipse Equivalent area diameter, bounding ellipse diameter, ellipsicity.Rectangle Bounding rectangle length, width, aspect ratio, rectangularity.Polygon Polygon order, convexity.

Fiber Length, width, aspect ratio, curl.Irregular Feret length, width, aspect ratio, mean radius, smoothness.

Figure 4/Table 1: An array of particle size descriptors can be determined by dynamic image analysis, depending on the particle shape model selected.

WHITEPAPER

5 of 14

Dynamic image analysis makes it quick and efficient to gather information about particle shape, increasing the practicality of studying its impact. The ability to visually scrutinize particles of interest is an added benefit. The technique is unaffected by particle properties so can be successfully applied to multicomponent blends, usefully providing differentiation on the basis of properties such as opacity as well as particle shape. As a number-based counting technique, dynamic image analysis is extremely sensitive to changes at the extremes of a particle size distribution, in the level of fines or coarse particles present.

DensityMotivation for measurement

When discussing correlations between density and product performance it is important to first consider definition of the term density. In fact, several density parameters can be usefully measured for pharmaceutical formulations, depending on the product and the behavior of interest. Density is, of course, mass divided by volume. The mass of a sample is unambiguous and relatively easily determined. It is different measurements of volume that give rise to alternative density parameters and these correlate with various aspects of pharmaceutical performance.

Envelope density: envelope density is determined using a volume defined by a smooth outline enclosing a product or solid sample, for example, a tablet or a sample of ribbon from a dry granulation compactor. Envelope density is indicative of the packing within the sample and the degree of voidage. The envelope density of a tablet can therefore be important from the perspective of hardness and dissolution performance. For a compaction ribbon envelope density is useful for assessing product consistency.

Bulk density: Uncompacted granules or powders contain solid particles that take up a packing arrangement dependent on their properties leaving voidage/interstitial volume within the sample. Bulk density is based on measurement of the total volume taken up by the sample, including both particle and interstitial volume. Volumetric dosing is a routine operation in pharmaceutical packaging, for example, in the manufacture of DPIs and capsules, but the intention is, in fact consistent mass dosage. Consistent bulk density is therefore essential. Similarly, bulk density is an important parameter from the perspective of die-filling in tableting, for the control of tablet weight. More broadly bulk density is indicative of packing behavior in a low stress or uncompacted state and can therefore help to elucidate flowability and other aspects of process behavior.

True or skeletal density: The final density parameter that may be of interest is that of individual formulation particles. For particles that are fully dense or have no accessible porosity then measurement of the volume of the particles within a sample produces true density (also referred to as absolute density). The volume of material in a sample of porous particles is smaller and associated with the metric skeletal density. For granules, it is these density parameters that may be controlled to produce desirable flow, compressibility or solubility characteristics. Particle density is also a critical determinant of segregation behavior with particles of disparate density more prone to separation.

Making measurements

Gas pycnometry, a displacement technique, is one of the most reliable and accurate methods for determining particle volume and by extension true or skeletal volume (see figure 5a), depending on the characteristics of the sample. Solid phase pycnometry, on the other hand, with a free-flowing quasi-fluid medium comprised of small rigid spheres, is an accurate and efficient technique for envelope density measurement (see figure 5b).

Figure 5a: In a gas pycnometry system the volume of the sample is determined by expanding the displaced gas into a second chamber...

Figure 5b: …while with solid phase pycnometry volume is determined by measuring the displaced volume of a free-flowing dry solid medium.

Dry Solid Medium

Precision BoreGlass Cylinder

Plunger Baseline: SolidMedium Only

in Cell

Measurement: SolidMedium and Object

in Cell

A Ah

B

WHITEPAPER

6 of 14

Gas pycnometry is a rapid, precise and highly automated technique, to the extent that it can be deployed at-line for process monitoring, for processes such as roller compaction. For pharmaceutical applications the combination of gas and solid-phase pycnometry can be particularly useful since envelope and true/skeletal density data can be combined to determine specific pore volume and average porosity. This is especially relevant for the characterization of tablets and roller compaction ribbons.

Equipment for bulk density measurement can be as simple as a graduated glass cylinder though instrumentation that permits some control over measurement conditions/packing state enables more reproducible and relevant measurement. Such instrumentation includes systems for solid-phase gas pycnometry which allow bulk density measurement under closely controlled consolidation conditions and for dynamic flow testing which enable bulk density measurement by a technique of sample conditioning and vessel splitting [6].

Surface areaMotivation for measurement

One of the primary motivations for measuring surface area is to define the potential for interaction between particles, or between solids and fluids. With respect to interactions between solids and fluids, surface area can be correlated with dissolution behavior, particularly in a compacted or granulated product when particle size may be less influential and surface area, along with porosity often provides more secure insight. Dissolution depends on the ability of the liquid, typically water, to access solid material which in turn relies on the amount of material exposed. Measurements of specific surface area quantify this, taking account of surface imperfections or voidage that enhance surface area beyond what might be predicted from particle size information alone. Such information can correlate directly with dissolution

performance and is especially useful in the development of products such as ODTs, orally disintegrating granules and effervescent tablets which are structured to dissolve rapidly.

Surface area is also an important parameter for lyophilized ‘cakes’ for reconstitution, where rapid and complete dissolution over a reasonable timeframe is essential. For these products, which typically have biological APIs, surface area is also a recognized factor in protein degradation reactions [7] and the likelihood of residual water getting trapped in the cake [8]; both of these issues can compromise product stability and safety. Surface area measurements can be directly helpful for optimizing lyophilization processes which tend to suffer from relatively poor energy efficiency.

Making measurements

Physical gas adsorption is the classical technique for quantifying the surface area of a solid. It involves measurement of the amount of gas that adsorbs onto the surface of a decontaminated sample as a function of pressure, using a gas adsorption apparatus (see figure 7), to produce an adsorption isotherm. Analysis of the isotherm using a suitable model, typically Brunauer, Emmett and Teller (BET) theory, enables the detailed characterization of surface area. Gas adsorption can be used to study materials with pores ranging from ~0.3nm to 300 nm in size.

Gas adsorption is the gold standard technique for surface area measurement and has a very wide measurement range that extends from the macroporous down into the microporous region. For pharmaceutical scientists the capability to study water sorption characteristics is an added benefit since this

Figure 6: Vessel splitting is an effective way of generating a precisely known powder volume and a level surface, for the accurate determination of bulk density.

“Warm” Volume

“Cold” Volume

Vacuum

Pressure= Pe

N2

Charging theManifold

Vacuum

Manifold Volume= Vm

Pressure= Pm

Volume= Vs

Pressure= Pi

Sample Tube

N2

LN2

Figure 7: With a gas adsorption apparatus the amount of gas physically adsorbed onto a sample is determined by measuring the equilibrium pressure that develops when a charged manifold (left) is opened to the sample (right).

WHITEPAPER

7 of 14

can be important for stability assessment. Water sorption experiments quantify directly how the product responds to humidity, providing useful information for stability, storage and coating requirements. For lyophilization applications, with the right gas adsorption apparatus (e.g. the ASAP 2460), it is now feasible to measure surface area in situ to provide much more representative data for product and process optimization than can be accessed via destructive testing, and traditional surface area measurement.

PorosityMotivation for measurement

Porosity, total porosity, and pore size distribution define the internal structure of granules and tablets. This is primarily of interest because of correlations with strength and fluid transfer.

For a finished tablet, porosity can influence mechanical attributes such as friability, hardness, and disintegration since these are all directly affected by the structure of the compact. Correlating porosity with these variables can therefore help with setting tableting parameters such as compaction/compression pressure to deliver a finished product with the required QTPP. Response to compression is, of course affected by the excipients in the formulation making porosity measurements valuable for excipient selection and for controlling granulation processes to produce a feed for the press that has acceptable compressibility.

Because pore size controls the ease with which liquid can penetrate the tablet, there are often direct correlations between porosity and dissolution. Indeed, porosity can often provide more fundamental insight into dissolution performance than dissolution testing, an analysis complicated by the need for dissolution media selection and set-up and the evolution of concentration profiles over time. Porosity data may therefore be used to define a product with acceptable dissolution performance in the development of conventional or effervescent tablets, ODTs or orally disintegrating granules. In addition, porosity data can provide an indicator of shelf-life and response to coating, by quantifying how easily water or coating molecules penetrate the tablet matrix.

Making measurements

The two most relevant techniques for measuring the porosity of pharmaceutical samples are mercury porosimetry and gas adsorption (as described above for surface area measurement).

Mercury porosimetry is based on measurements of the amount of mercury forced into a sample as a function of pressure (see figure 8). The underlying measurement principle is the correlation between pore size and the pressure required for pore-filling, which is described by Washburn’s equation. The technique offers an unrivalled dynamic range – from a pore size of ~3nm to ~0.9mm – and can be used to generate detailed information about porosity including pore size distribution, total pore surface area, median pore size, tortuosity, and information about pore shape.

Gas adsorption measurements for porosity determination are strictly analogous to those for surface area though measurements are be made up to higher pressures, to ensure complete filling of the pores of the sample. The resulting data are then analyzed using an appropriate method such as that of Barrett, Joyner and Halenda, which is well-suited to mesoporous materials (pore size 2 – 50 nm).

Mercury porosimetry offers speed and accuracy and provides more detailed porosity information that can be generated from other techniques. On the other hand, gas adsorption has the advantage of a more benign health and safety profile and the ability to characterize microporous materials which can be a requirement in certain instances.

Pressure applied at this end

Glass

Capillary Tube(Stem)

Sealed Sample Cup

Sample

Electrical Contact

Cap

Mercury

Metal Plating

Cross-Sectional View of aMercury Penetrometer

Figure 8: Mercury porosimetry involves measurement of the pressure required to force mercury into the pores of a sample.

WHITEPAPER

8 of 14

FlowabilityMotivation for measurement

The flowability of a pharmaceutical formulation determines the ease and consistency of powder movement through a process and is therefore of direct interest from the perspective of manufacturing efficiency. However, by influencing process performance flowability can also impact the quality and characteristics of the finished product.

For example, in tableting, consistent, controlled powder flow, from the feed hopper, into the feed frame and to the tablet die is essential. Enhancing flow properties via the use of flow additives and/or granulation is often essential to ensure complete die-filling and, by extension, the production of high-quality tablets of uniform weight. Flowability is similarly relevant to the attainment of consistent dosing when filling sachets or capsules, with technologies such as vacuum vial filling and dosator systems calling for the exacting optimization of flow properties. Here, a formulation that flows relatively freely under low stress conditions aids extraction of the dose from the powder bulk but a degree of cohesivity is essential to ‘lock’ the volumetric dose for secure transfer into packaging.

Flowability also has demonstrated relevance to blending performance and the dispersion behavior of DPI formulations [9,10]. The optimal time and conditions required to blend APIs and excipients to homogeneity are directly dependent on the dynamic flow properties of constituent powders in a blend. With respect to DPI formulations, measurements of aerated flow properties, which quantify cohesion in the formulation, have been correlated directly with fine particle dose, the amount of drug delivered within a respirable size range.

Making measurements

Of the many techniques available for measuring the flow properties of powders, dynamic powder testing has proven to be the most sensitive and relevant method for pharmaceutical applications. Dynamic properties are generated from measurements of the axial and rotational forces acting on a blade as it rotates through a powder sample along a precisely defined path (see figure 9). Powders can be tested in a consolidated, moderate stress, aerated or fluidized state to generate parameters of direct relevance to specific applications and processes.

Alternative techniques include shear cell testing, uniaxial testing and powder strength testing, all of which generate values of unconfined yield strength (UYS), an intrinsic powder property that defines the strength of interactions between powder particles, and by extension flow function (FF). In shear cell testing, the force required to shear one consolidated powder face relative to another is measured and UYS is determined by a process of mathematical extrapolation. In uniaxial testing, in contrast, yield strength is measured directly by fracturing a freestanding, uniformly consolidated powder column through the application of a vertical stress. Powder strength testing is also a direct technique with centrifugal force applied to consolidate and fracture the sample. Though each technique measures yield strength, the absolute values generated differ in each case because of the measurement conditions applied.

Shear cell analysis was developed to support a more scientific approach to hopper design. It remains useful for this application and more broadly for investigating powder flow behavior in a moderate to high stress environment. However, for flowability ranking, uniaxial testing offers high repeatability and reproducibility and much faster measurement times. Powder strength testing, on the other hand, offers the advantages of small sample size and the capability to measure at relatively low consolidation pressures. This can make it a valuable option for characterizing APIs.

Dynamic testing offers far greater capacity to tailor the test environment and gather relevant information than any other technique and can robustly differentiate samples that other test methods, including shear cell analysis classify as identical. The ability to directly assess how a powder responds to air can be especially valuable for

Total Flow Energy= Area Under Curve

ENER

GY

GR

AD

IEN

T m

l/m

m

TORQUE

H1FORCE

H1 HEIGHT H2

H2

Figure 9: Dynamic powder testing quantifies flowability and can be used to characterize powders in a consolidated, moderate stress, aerated or fluidized state.

WHITEPAPER

9 of 14

pharmaceutical applications, for example, when investigating the performance of inhaled formulations or the ability of a tablet blend to release air prior to compression. Instrumentation for the measurement of dynamic properties (as exemplified by the FT4 Powder Rheometer), also has the capability for shear cell testing and to measure bulk properties such as compressibility, permeability and bulk density. It can therefore provide comprehensive, multi-faceted powder characterization to optimally supports pharmaceutical development and manufacture.

Bulk powder propertiesMotivation for measurement

In addition to the bulk powder properties already discussed – bulk density and flowability – several others are helpful in elucidating the performance of pharmaceutical products and processes. These include: compressibility; permeability; and propensity to segregate.

Compressibility is primarily of interest for predicting response to compaction – either in a tablet press or roller compactor. Measurements therefore inform both formulation and design space scoping. Beyond that, compressibility can be illuminating in process troubleshooting with more compressible powders prone to exhibit change as a result of consolidation under their own weight.

Permeability quantifies the resistance of a powder to air flow. It is an important parameter for tableting formulations as air retained through the compression step, as a result of low permeability, can result in capping or lamination of the finished product. Permeability is also important in material transfer, particularly pneumatic and vacuum transfer, and in filling and discharge since it defines the ease with which air can ‘back flow’ out of a die or container as the powder enters. Poor permeability is a known cause of low and/or pulsatile flow during hopper discharge.

Though not strictly speaking a ‘bulk property’ the propensity of powder blends to segregate is of critical significance in pharmaceutical applications because of the need for uniform distribution of the API to ensure consistent dosing. API particles are often very fine and, due to their potency, dispersed in very low levels in a coarser excipient; blends with dissimilarly sized particles are particularly prone to segregation.

Making measurements

Compressibility is quantified from measurements of bulk density as a function of applied normal stress while permeability is determined from measurements of the pressure drop across a powder bed when air is forced through it at a defined flow rate (see figure 10 upper and lower). Pressure drop is measured with respect to applied normal pressure with Darcy’s Law correlating permeability with air flow rate, bed height and pressure drop.

Segregation can be detected through repeat measurements of dynamic flow properties since it typically leads to changes in flow behavior. This can be a simple way to generate process relevant data since it offers some insight into how segregation is likely to impact the process. However, with many industries sharing the need to elucidate and address segregation behavior, analytical solutions have been developed specifically to address the issue, as exemplified by the SPECTester. This spectroscopic instrument identifies the extent of segregation in a blend containing up to 6 components, elucidating the mechanisms of segregation and differentiating components that are separated more easily from those with a greater tendency to remain uniformly dispersed.

Figure 10: Compressibility (upper figure) is defined as change in bulk density as a function of applied normal stress while permeability is determined from measurements of the pressure drop across a packed bed when air flows through it a defined rate (lower figure).

Normal Stress σ

Air in Air in(a

ir pr

essu

re d

rop

acro

ss p

owde

r bed

)

Increasing Normal Stress, σ

σ

Normal Stress σ

COHESIVE POWDER Height

Nor

mal

Str

ess,

σ

δh

WHITEPAPER

10 of 14

Case study 1: Correlating granule flowability and tablet hardnessIn an experimental study using a ConsiGma-1™ continuous granulation/drying system (GEA Pharma Systems), four batches of granules were produced with a N-acetyl-p-aminophenol [APAP]-based formulation. Processing conditions were manipulated on the basis of previous scoping studies [11] to produce granules with specific flow properties, as defined by Basic Flowability Energy (BFE), a dynamic powder flow property; Table 2 shows the process parameters applied. The flow properties of the granules were measured (FT4 Powder Rheometer®, Freeman Technology) after each stage of the manufacturing process: for the granulated wet mass; after drying; after milling; and after the granules had been lubricated as a precursor to tableting. BFE values were measured three times for each set of process conditions. To assess any correlation between granule flow properties and tablet quality the granules were processed to tablets using a GEA Modul™ S rotary tablet press. The hardness of the resulting tablets was measured and is presented as an average of 10 measurements.

This study illustrates the principle of manipulating processing conditions to produce granules with a specific flowability. Wet granules with a relatively low BFE were produced using conditions 1 and 2, while a higher BFE was targeted with conditions 3 and 4. These conditions were set on the basis of scoping studies exploring the impact of variables such as screw speed, manufacturing (feed) rate and water content and led to the successful production of two comparable sets of granules, using two quite different sets of processing conditions in each case. Drying accentuates the difference in flowability between the two sets of granules, while milling and lubrication erodes it, but at all stages the BFEs of the granules produced under Conditions 3 and 4 are consistently higher than those produced using Conditions 1 and 2 (see figure 11).

The results show an extremely strong correlation between tablet hardness and BFE for the dried and milled granules (R2>0.99). The correlation with BFE for the wet mass and lubricated granules is slightly weaker, though still significant, a result that can be attributed to the complicating impact of water/lubricant which are known to have an exaggerated impact on bulk flow properties at low concentrations (see figure 11).

In summary this study demonstrates that:

• Targeting a BFE set point allows the operator flexibility over granulation parameters

Screw Speed (RPM)

Powder Feed (hg/hr)

Liquid Feed (g/min) Moisture (%)

Condition 1 450 11.25 15 8

Condition 2 750 20 36.7 11Condition 3 450 6 20 20Condition 4 750 9 30 20

Table 2: Granulation conditions were selected to produce granules of higher (conditions 3 and 4) and lower (conditions 1 and 2) flowability.

BET

, mJ

0

1000

2000

3000

4000

5000

Wet Dried Milled Lubricated

Condition 1

Condition 2

Condition 3

Condition 4

Tablet Hardness vs BFE of Wet, Dried, Milled & Lubricated Granules

y= 0.0135x - 12.383R2= 0.7965

y= 0.0061x - 1.0714R2= 0.9912

y= 0.00041x - 1.5719R2= 0.8717

y= 0.0018x + 3.9446R2= 0.9926

Wet Mass

Dried Granules

Milled Granules

Lubricated Granules

Basic Flowability Energy mJ

Tabl

et H

ardn

ess,

kPa

0

4

6

8

10

12

14

16

500 1000 1500 2000 2500 3000 3500 4000 50004500

Figure 11: Granules of different flowability can be robustly targeted through the manipulation of processing parameters (top). There is a direct correlation between granule flowability and tablet hardness (bottom).

WHITEPAPER

11 of 14

• Granules with a specific BFE go on to produce tablets of defined hardness.

This illustrates the value of BFE as a repeatable, measurable variable for design space definition and process control for pharmaceutical granulation.

Case study 2: Investigating the impact of temperature on the specific surface area of excipientsOften the precise mechanism(s) by which excipients confer advantageous properties such as enhanced flowability or lubricity are not fully understood though the parameters that influence their performance may be clear. This is the case for magnesium stearate (MgSt) a relatively complex material that impacts lubricity via mechanisms that remain subject to investigation [12], but for which specific surface area is important in defining behavior, as reflected in the USP standard for the material [13]. Where specific surface area defines performance, understanding the impact of temperature is critical. In an experimental study, tests were carried out to assess the effect of sample preparation temperature on the specific surface area of a range of excipients, to provide insight for gas adsorption method development; the resulting data provide to inform the effective commercial use of these important industrial materials.

Samples of Al2O3, SiO2, stearic acid, MgSt, and Lactose were prepared for gas adsorption. This involved holding the sample at a defined temperature in the range 20 to 120°C (depending on the material under test) for 12 hours, under vacuum, to remove moisture, solvents, and any ambient gases. Gas adsorption measurements were then made using standard test protocols, with nitrogen as the sorptive gas (TriStar II, Micromeritics). The BET model was applied to determine specific surface area data from the resulting isotherms.

Data for the two oxides show that specific surface area increases with preparation temperature though the effect is most marked for Al2O3, which shows an increase of around 33% across the temperature range (see figure 12); for SiO2 the more modest rise begins to level out at higher temperature. The results observed for Al2O3 are attributed to the removal of CO2 at higher temperatures; water removal gives rise to the increase in surface area observed with the SiO2.

Data for stearic acid and MgSt, in contrast, show a reduction in specific surface area with increasing temperature. For MgSt there is a decrease of around 20% across the temperature range; for stearic acid, the relatively dramatic change that occurs over a narrower temperature range is indicative of melting. For both compounds elevated temperature promotes a transition from smaller to larger particles, and an associated decrease in surface area, via melting, sintering, dehydration and decomposition processes.

Figure 12: Data for SiO2 (left) and Al2O3 (right) show that both oxides exhibit an increase in specific surface area with increasing preparation temperature, though the increase for Al2O3 is substantially more significant.

Figure 13: In contrast to the oxides, stearates exhibit a reduction in specific surface area with increasing preparation temperature.

Figure 14: The specific surface area of lactose increases with preparation temperature, but to a maximum level.

WHITEPAPER

12 of 14

Finally, with lactose we see a further form of behavior. Here specific surface area again increases with temperature, peaking at around 90 – 100°C after which there is no further rise.

These results illustrate the importance of measuring specific surface area under representative conditions and the potential to vary temperature to control specific surface area and by extension the performance of excipients.

Case study 3: Establishing specifications for vendor qualificationIncreasingly complex supply chains have become an established part of the pharmaceutical landscape in recent years making it crucial for manufacturers to be able to robustly differentiate supplies to select a vendor with confidence. While materials necessarily meet a market specification this may not include parameters that are influential in defining process performance, a topic discussed in reference 14 which highlights the potential benefits of flowability testing within the context. Measuring samples

with an extended ‘toolkit’ or with enhanced sensitivity are both valuable strategies when it comes to vendor selection.

In this experimental study three lots of three commercially available excipients were subject to extensive testing to rigorously assess variability, simulating a vendor qualification study. The materials tested were: anhydrous lactose (SuperTab 21AN), spray-dried lactose (SuperTab 11SD), and microcrystalline cellulose (Pharmacel 101) (all DFE Pharma). The following parameters were measured using the standard methodologies associated with the instrumentation:

• Particle size distribution by laser light scattering (Saturn DigiSizer II)

• True/skeletal density by helium pycnometry (AccuPyc 1340)

• Porosity by mercury intrusion porosimetry (AutoPore IV 9500)

• BET specific surface area using krypton gas (ASAP 2420 Surface Area Analyzer)

MATERIAL LOTPARTICLE SIZE (VOLUME DISRIBUTION)

MEAN D90 D50 D10

SuperTab 21AN

10678881 132.874 299.980 118.163 1.286

10640579 123.902 278.460 111.460 1.184

10680069 137.314 298.012 128.024 1.399

Mean 131.363 292.151 119.078 1.290

%RSD 5.2 4.1 7.2 8.3

SuperTab 11SD

10614997 59.168 117.334 53.639 4.146

10643209 67.634 124.826 65.090 11.091

10641963 69.883 136.195 64.786 7.324

Mean 65.562 126118 61.172 7.520

%RSD 8.6 7.5 10.7 46.2

Pharmacel 101

00100016 51.810 98.606 49.353 7.824

00100014 55.109 103.303 53.231 9.020

00100018 57.587 105.306 56.397 11.028

Mean 54.835 102.405 52.994 9.291

%RSD 5.3 3.4 6.7 17.4

Table 3: Particle size distribution data for the three excipients shows greater variance at the edges of the distributions.

WHITEPAPER

13 of 14

Particle size is a relatively standard specification for a powder excipient and static light scattering is a routine technique for measurement. However, the instrument used here offers more precise resolution that many commercial systems because of the CCD detector used, particularly at the extremes of the particle size distribution. The reported %RSDs are quite high for all materials, arguably much higher than would be expected, with the greatest variation seen in the D10 figure that quantifies fines; mean values

are far more consistent (see table 3). Here it is likely that the instrument is detecting far greater variance than the manufacturer may be aware of which begs the question of is it important to be able to differentiate materials in this way? The answer to that question is application specific. If the process is very sensitive to fines, then the high %RSD for D10 for SuperTab 11SD may be problematic; for other processes the lot-to-lot variation may not be an issue.

MATERIAL LOT DENSITY POROSITY SURFACE AREA (m2/g)

SuperTab 21AN

10678881 1.5821 8.5783 0.3490

10640579 1.5810 8.5917 0.3442

10680069 1.5798 11.1114 0.3452

Mean 1.5810 9.4271 0.3461

%RSD 0.07 15.5 0.73

SuperTab 11SD

10614997 1.5389 3.4083 0.2172

10643209 1.5391 2.8102 0.2207

10641963 1.5384 3.0303 0.1892

Mean 1.5388 3.0829 0.2090

%RSD 0.02 9.8 8.26

Pharmacel 101

00100016 1.5495 18.694 1.3805

00100014 1.5545 16.3986 1.3345

00100018 1.5527 16.9754 1.3792

Mean 1.5522 17.3561 1.3647

%RSD 0.16 6.9 1.92

Table 4: Measuring a wide range of properties provides a more robust test of equivalence in vendor qualification.

Table 4 includes properties that may not be reported routinely in a specification, or more importantly, measured or controlled during manufacture. Density and specific surface area values are, in general, highly consistent, except for the SuperTab 11SD which has a relatively high %RSD for specific surface area. However, with all three substances porosity, as quantified by mercury porosimetry, shows significant variance. Mercury porosimetry is not a popular technique for the industry because of its health and safety profile so this may well be a variable not routinely assessed. Again, whether the detected variability is problematic, is entirely dependent on the process/application of interest.

In summary, these tests show that by applying more sensitive instrumentation, or instrumentation not routinely used to characterize a material, it may be possible to differentiate supplies that are notionally identical to more rigorously assess the quality provided by a specific vendor. This offers opportunities to optimize cost/performance decisions to build a stronger more robust supply chain or to put in place testing to ensure more effective raw material control.

WHITEPAPER

14 of 14

In conclusionThe uptake of QbD has led to an increased appreciation of the many benefits and reduced risk associated with a thorough understanding of process and product behavior. Analytical data provide a foundation for that understanding and drive efficient progress in formulation and manufacture. This paper highlights the physical characterization techniques that are essential in elucidating the performance of solid dosage forms, most especially in defining the properties of finished products that determine critical attributes such as stability, disintegration and dissolution behavior. Leveraging techniques and instrumentation that efficiently deliver robust and relevant information makes it easier to adopt the knowledge-led approach enshrined in QbD while minimizing the effort and cost associated with doing so.

References:[1] T. Hein ‘Top form: The benefits of multiple oral

solid dosage forms’ European Pharmaceutical Manufacturer, 25th Jan 2017, Available to view at: https://www.epmmagazine.com/news/top-form-the-benefits-of-multiple-oral-solid-dosage-forms/

[2] N. Damodharan Dosage Forms Unit I. Presentation available to view at: Available to view at: http://www.srmuniv.ac.in/sites/default/files/downloads/Dosage_forms.pdf

[3] ICH Harmonised Tripartite Guideline Pharmaceutical Development Q8 (R2), August 2009.

[4] J. Maguire and D. Peng ‘How to Identify Critical Quality Attributes and Critical Process Parameters’ Presentation delivered at 2nd FDA/PQRI Conference, Oct 2015. Available to view at: http://pqri.org/wp-content/uploads/2015/10/01-How-to-identify-CQA-CPP-CMA-Final.pdf

[5] ICH Harmonised Tripartite Guideline Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. Q6A October 1999

[6] The Definitive Guide to Powder Characterization Whitepaper. Available to view at: https://www.micromeritics.com/Product-Showcase/Powder-Characterization.aspx

[7] A. Siew ‘Freeze Drying Protein Formulations’ 2nd May 2014, Pharmaceutical Technology. Available to view at: http://www.pharmtech.com/freeze-drying-protein-formulations

[8] FDA ‘Guide to Inspections of Lyophilization of Parenterals’ Last updated 11/25/2014. Available to view at: https://www.fda.gov/iceci/inspections/inspectionguides/ucm074909.htm

[9] J. Shur et al ‘Fine Tuning DPI Formulas’ Manufacturing Chemist June 2008

[10] T. Freeman and B. Armstrong ‘Using powder characterisation methods to assess blending behaviour’ Whitepaper available to view at: https://www.freemantech.co.uk/literature/white%20papers/Using_powder_characterisation_methods_to_assess_blending_behaviour.pdf

[11] T. Freeman, A. Birkmire and B. Armstrong ‘A QbD approach to continuous tablet manufacture’ Procedia Engineering 102 ( 2015 ) 443 – 449.

[12] S. P. Delaney et al. ‘Characterization of Synthesized and Commercial Forms of Magnesium Stearate using Differential Scanning Calorimetry, Thermogravimetric Analysis, Powder X-ray Diffraction, and Solid-State NMR Spectroscopy’ Journal of Pharmaceutical Sciences 106 (2017) 338 – 347.

[13] USP Stage 6 Harmonization Document. Magnesium Stearate. August 2016. Available to view at: http://www.usp.org/sites/default/files/usp/document/harmonization/excipients/magnesium.pdf

[14] T. Mollner ‘Why powder testing is a powerful tool for healthcare’ European Pharmaceutical Manufacturer 30th Jan 2019. Available to view at: https://www.epmmagazine.com/news/why-powder-testing-is-a-powerful-tool-for-healthcare/