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SAutoFlow BET+ Srface area analyzer

Applications of Interest to the Pharmaceutical Industry




Surface area is an important physical property that determine the performance characteristics of pharmaceutical powders, ingredients, API’s, and excipients. Differences in the surface area and porosity of particles within the material, which otherwise may have the same physical dimensions, can greatly influence the performance characteristics important for pharmaceutical products. Surface area plays a major role in the purification, processing, blending, tableting and packaging of pharmaceutical products. It also can impact the drug’s useful shelf life, its dissolution rate and bio-availability. The use of materials with well-defined pore sizes and high surface areas are often used in biochemical and pharmaceutical separation sciences.

Gas Adsorption analysis is often used for surface area and porosity measurements within the pharmaceutical industry. The Brunauer, Emmett and Teller (BET) technique is commonly used for determining the surface area of pharmaceutical powders and porous materials. This technique involves exposing solid materials to gases or vapors at a variety of conditions and evaluating either the weight uptake or the sample volume. Analysis of this data provides information regarding the physical characteristics of the solid including specific surface area, porosity, total pore volume, and pore size distribution. Gas sorption can also provide valuable information on the physical structure and shape of the pores.

Gas adsorption analysis can also give insight into the surface roughness of a pharmaceutical product. The performance characteristics of pharmaceutical products such as oral tablets, and dry powders for inhalation can be influenced by surface roughness. Critical performance qualities such as dissolution, stability, friability, adhesion of coatings, blend homogeneity, particle to particle adhesion, powder flow, and powder packing are impacted by surface areas. In the case of dry powder inhalation (DPI) formulations surface roughness can affect the interaction between the small drug particle, and the larger inert carrier particles.

Many of Quantachrome’s gas sorption analyzer family have been designed for use in cGMP compliant facilities, and provide built in software tools to comply 21 CFR Part 11 guidelines.


Application Notes:
"Magnesium Stearate: Solving the Surface Area Problem " (Nova e) A briefing/summary of a Quantachrome case study discussing the magnesium stearate surface area problem.

Surface Area: The Most Underutilized Particle Property in Pharma? Reprint from PharmaFocus outlining the importance of surface area for the pharmaceutical industry

Pharmaceutical | Instruments | Standards


In the preparation and distribution of pharmaceuticals the susceptibility of the active ingredients, excipients, and end products to moisture is of primary concern. Excessive moisture in the preparation process can affect the quality of the product and moisture adsorbed in the shipment and storage of the products can degrade the effectiveness or even contaminate the drugs. This can be mitigated through control of the environmental conditions of production, tailoring the excipients to be moisture resistive, and/or encapsulation to exclude moisture. However, a reliable means of evaluating and controlling these measures is needed and water vapor sorption instruments are the answer.

ShelfLife

Ambient moisture can be adsorbed and absorbed by pharmaceuticals during storage and shipment, increasing the formation of microbial contamination and decreasing the potency of the drugs. Through carefully designed packaging, selection of excipients, and encapsulation this can be controlled. Measuring the amount and rate of water sorption is an excellent tool in evaluating the effectiveness of these measures and verifying the consistency of the end product.

Quantachrome Instruments for water sorption analysis are the Aquadyne DVS and VSTAR.

    Pharmaceutical | Instruments | Standards


    Water Sorption Rates

    The rate at which a material gains or loses water is often more important than the static water activity. Over time, unless hermetically sealed, pharmaceuticals will either gain or lose moisture to achieve equilibrium with the environment. Design of packaging is critical in slowing this exchange of water, but once the package is opened it is desirable for this exchange to occur as slowly as possibly. Measuring the rates of water sorption under various humidity conditions can help drug designers optimize the formulations and increase the length of time a pharmaceutical remains potent after opening. The Aquadyne DVS can control the temperature and relative humidity, while continuously measuring the mass change (due to gain or loss of water) over time. This kinetic information can also be obtained using the VSTAR vacuum-volumetric vapor analyzer. Vacuum-volumetric (manometric) analyzers are typically faster than gravimetric analyzers, since in gravimetric analyzers the water has to compete with the carrier gas to reach the surface and diffuse into the sample. However, gravimetric systems more closely simulate “real world” conditions of drug handling and storage.

    Quantachrome Instruments for water sorption analysis are Aquadyne DVS and VSTAR.

     

     

    In the choice of excipients and the formulations of coatings the hydrophilicity is a major factor. The product must be resistant to moisture to ensure a reasonable shelf life, but must also dissolve readily when taken orally. A hydrophilicity index, as proposed by Thommes et al, provides a means of quantitatively determining a material’s affinity to water by comparing the pore volume from N2 at 77K or Ar at 87K to the volume of water adsorbed. The closer this index is to 100% the more hydrophilic the material is.

    Quantachrome Instruments for water sorption analysis are Aquadyne DVS and the VSTAR.
    Quantachrome Instruments for micropore volume determination are Autosorb 6iSA, Quadrasorb evo, and Autosorb iQ.


    Cited Paper:
    Thommes, M., Mitchell, S., Pérez-Ramírez, J., Surface and Pore Structure Assessment of Hierarchical MFI Zeolites by Advanced Water and Argon Sorption Studies, The Journal of Physical Chemistry C 2012 116 (35), 18816-18823. http://dx.doi.org/10.1021/jp3051214

 

In characterizing pharmaceuticals and excipients it is sometimes useful to perform an adsorption-desorption experiment under fixed time conditions, rather than under fully equilibrated conditions. The kinetic plots resulting from these experiments form “fingerprints” that contain information about the affinity to water and the rate of sorption at several relative humidities that is characteristic to the sample. An example of one such plot is shown below:


The kinetic plots resulting from these experiments form “fingerprints”

Relevant Tech Note:
#56 Water Vapor Sorption by Active Pharmaceutical Ingredients.

Quantachrome Instrument for water sorption analysis at various relative humidities is the Aquadyne DVS .

Prior to conducting any type of analytical tests on powdered materials it is important to assure that the sample being tested is representative of the larger quantity of material that it came from (“representative sampling”). Over time due to a variety of physical factors a larger sample of powdered or granular materials might have differences within itself. One reason is that, in general, particles tend to segregate such that the finer ones settle toward the bottom of the container. This phenomena is caused by the smaller particles falling through the voids between the larger ones. Heaps also tend to accumulate larger particles towards the outside as they roll over smaller particles. The goal of representative sampling is to eliminate between sample variation that might cause variances in analytical results independent of the characteristics of the underlying sample. A commonly used technique to assure homogeneity is via combining and splitting of samples.

There are many methods of conducting splitting for representative sampling, but one of the most efficient commonly used in the pharmaceutical industry for powdered and granular materials is by using a rotary riffler. A rotary riffler is a mechanical device that will evenly split samples into multiple sample ports. This device uses mechanical energy to provide a constant and even flow of material from its sample holder. The steady flow passes through a divider head operating at constant speed (adjustable). Through further splitting and recombination of the smaller samples it is possible to assure that the subsamples are representative of the larger samples.


Instruments:Micro Rotary Riffler.


Technical Literature
NIST Recommended Practice Guide Publication, 960-17, Porosity and Specific Surface Area Measurements For Solid Materials- See pages 18-20 for representative sampling recommendations.

H.G.Brittain (2002) Pharm. Tech., July ‘02, 67-73, Particle Size Distribution II- The Problem of Sampling Powdered Solids.

Tech Note:
Quantachrome Powder Tech Note #5- Representative Sampling for Surface Area Measurements


Rotary Riffler Demonstration- Video of Rotary Riffler Demonstration

    Pharmaceutical | Instruments | Standards


    Hydroxyapatite Ca10(PO4)6(OH)2

    A porous biocompatible ceramic.The basic calcium phosphate known as hydroxyapatite (HAp) is used in a number of essential applications. Probably the most well known is its use in the biomaterial field. It is essentially the hard component of bone, so products made of HAp are widely used in-vivo. Porous HAp shapes can be used as bone substitutes in reconstruction. The porosity is essential to allow access to fluids and tissue and bone ingrowth. HAp also exhibits ion-exchange (IE) properties and is used in IE and protein affinity chromatography. Substituted HAp can be used as an oxidative coupling catalyst, or straight HAp can be used as a catalyst support. Apart from the chemistry of HAp’s surface, therefore, it is important to know and to control surface area, pore size and pore volume since these parameters control adsorption capacity and biocompatibility.

    Suggested Reading

    "Adsorption on and Surface Chemistry of Hydroxyapatite

    Fifteen Years of Clinical Experience with Hydroxyapatite Coatings in Joint Arthroplasty"

    "Hydroxyapatite and Related Materials"

    "CRC Handbook of Bioactive Ceramics, Volume II"

    "Bioceramics (Advanced Ceramics)"

    "Bioceramics: Materials, Properties, Applications"

    "Progress In Bioceramics"

    "Bioceramics: Materials and Applications III"

    "Affinity Chromatography"

    Surface Area

    The preferred method of measurement is gas adsorption. Given the surface irregularity of real powder particles, not withstanding the presence of pores, the practice of calculating surface area from particle size normally resulting in a severe underestimation of the true surface area. Furthermore, gas adsorption is the only technique that can properly access internal surface, i.e. that which is due to the presence of pores. Modern automatic instruments like the NOVA make this determination rapid and user-friendly


    Pore Size

    Not only do pores express surface area and internal volume, their size controls accessibility to that space. Both cells and proteins range from nm- to micron size therefore biocompatible HAp’s tend to have pores on this scale. The most appropriate technique for measurement of these pore sizes is mercury intrusion porosimetry. Porosimeters such as the PoreMaster rapidly (< 30 mins.) measure a complete pore size distribution from ca. 900 microns to as small as 0.4nm. Gas sorption (see surface area, above) is also widely used for pore size measurement, especially for pores <0.4nm, but cannot be usefully employed for pores > ca. 0.4 microns.


    Porosity

    It may be sufficient to know just the porosity of a sample, i.e. the pore volume expressed as a fraction, or percentage, of the total bulk volume. The total pore volume can be determined directly by mercury intrusion, or can be calculated as the difference between bulk volume and true (skeletal) volume. Bulk volume can be calculated from external dimensions for simple geometric shapes, or by dry powder pycnometery (displacement) for irregular objects or particles that are too small to determine geometrically. Dry powder pycnometery is performed using a powder-tapping device like the Autotap. This instrument is also used to determine the bulk density and compression behavior (under vertical oscillation) of loose powders. True density is measured cleanly and quickly by gas pycnometry, fully automatically.


    Abbreviated Quantachrome Density Reference List

    These papers cite the use of Quantachrome's products and the list represents a fraction of all such papers. If you would like more examples, please contact us.

    "Calcium phosphate and fluorinated calcium phosphate coatings on titanium deposited by Nd:YAG laser at a high fluence" D.Ferro, S.M.Barinov, J.V.Rau, R.Teghil and A.Latini (2005) Biomaterials, 26, 805-812.

    "Bioactive coatings prepared by sol–gel on stainless steel 316L" C.García, S.Ceré and A.Durán (2004) Journal of Non-Crystalline Solids, 348, 218-224.

    "Strength and toughness of tape cast bioactive glass 45S5 following heat treatment" D.C.Clupper, L.L.Hench and J.J.Mecholsky (2004) Journal of the European Ceramic Society, 24, 2929-2934.

    "Fused deposition modeling of novel scaffold architectures for tissue engineering applications" I.Zein, D.W.Hutmacher,K.C.Tan and S.H.Teoh (2002) Biomaterials, 23, 1169-1185.

    "Fabrication of hydroxyapatite bodies by uniaxial pressing from a precipitated powder L.M.Rodriguez-Lorenzo, M.Vallet-Reg and J.M.F.Ferreira (2001) Biomaterials, 22, 583-588.

    "Sol-gel derived carrier for the controlled release of proteins E.M. Santos, S.Radin and P.Ducheyne (1999) Biomaterials, 20, 1695-1700

    Due to copyright restrictions, Quantachrome cannot supply copies of the above papers but we will be pleased to direct you the the appropriate authors so you may make your request to them. Ask here.


    Standards (methods, specifications etc.)

    Click on links below to order online / download. Note: provision of these links does not imply that Quantachrome's products are suitable for all of stated methods. This feature is provided as a convenience to those interested in hydroxyapatite and bioceramics. Quantachrome cannot entertain any questions regarding proper use of those standards not appropriate for Quantachrome's products. In such cases, you should contact the publishers.

    Implants for surgery. Hydroxyapatite. Ceramic hydroxyapatite, BS ISO 13779-1:2000 Implants for surgery.

    Hydroxyapatite. Coatings of hydroxyapatite, BS ISO 13779-2:2000

    Standard Specification for Composition of Hydroxylapatite for Surgical Implants, ASTM F1185-03 (2003), ASTM International