Using Vapor Sorption Techniques to Identify and Characterize Pharmaceutical Materials

Most pharmaceutical materials can exist in a desired crystalline state with an ordered lattice structure. There are several different crystalline forms of the same material available, such as polymorphs and/or solvated crystal forms.

However, there will generally be one thermodynamically preferred crystal structure with the lowest energy; all other forms are considered metastable, and eventually settle down to the more stable form.

While processing pharmaceutical solids, different degrees of disorder, such as crystal defects and/or amorphous regions, will be generated. In rare cases, the material can become completely amorphous, though this is rare as there is no longer any long-range structural order, which can cause complex and challenging problems with regards to the performance, processing, and storage of pharmaceutical formulations. The presence of amorphous material in low levels (<10%) may negatively affect the stability and manufacturability of the formulated drug product.

Disordered materials are metastable in nature and have the tendency to return to the more thermodynamically stable, crystalline form upon receipt of thermal or mechanical energy.

Hence, it is necessary to study the level of disorder or thermodynamic state of pharmaceutical materials in their formulation, storage and processing. This article discusses the application of vapor sorption techniques in the analysis of pharmaceutical solids.

Dynamic Vapor Sorption (DVS) and Inverse Gas Chromatography (IGC SEA) are proven techniques to determine surface and bulk properties of films, fibers, and powders. The objective of this article is to highlight the use of these techniques as they are connected with thermodynamic stability in pharmaceutical materials.

DVS and IGC SEA Methods

The interaction of water with pharmaceutical materials has been studied using gravimetric vapor sorption techniques. DVS is a proven technique to determine vapor sorption isotherms. The DVS quantifies the sample mass change when the vapor environment surrounding the sample is changed in a controlled manner.

Vapor sorption leads to mass increase and vapor desorption results in mass reduction. Electronic mass flow controllers are used to mix saturated and dry carrier gas streams for controlling vapor concentration around the sample.

IGC SEA is the inverse of a traditional GC experiment. However, IGC SEA is not an analytical method like GC, but a physico-chemical characterization technique. An IGC SEA experiment involves packing or coating a column with solid material of interest, normally a powder, coating, film or fiber.

Then, the column is fed with a pulse or constant concentration of a known vapor or gas probe at a fixed carrier gas flow rate to measure the retention behaviour of the pulse or concentration front using a detector.

A chain of IGC SEA measurements is performed with various gas or vapor phase probe molecules to get access to a variety of physicochemical properties of the solid sample. Retention volume (V_N) is the fundamental parameter used to derive most of the physicochemical properties, and is a measure of the degree of interaction of a specific probe molecule with the solid sample. Physical properties of a pharmaceutical material, such as the surface energy and solubility parameter, can be derived from V_N.

Crystalline Materials

The most thermodynamically stable form of a pharmaceutical solid will have the lowest energy value when compared to other less stable forms. As shown in Figure 1, crystals sieved to various particle size fractions provided the same dispersive surface energy values. Hence, besides particle size, changes in surface chemistry or orientation of surface groups will also be the reason behind surface energy changes.

Figure 1. Dispersive surface energy values for α-lactose monohydrate crystals at different particle size fractions

Polymorphs

Polymorphism is the ability of a material to exist as two or more crystalline phases with specific arrangements of crystal lattice, and is common in most pharmaceutical solids.

Since physical and mechanical properties will be different for different polymorphs, it is important to characterize different polymorphic forms to develop stable drug products.

Polymorph characterization can be done using both IGC SEA and DVS. IGC SEA surface free energy measurements are more suitable for polymorph analysis due to the fact that free energy values vary for different polymorphic forms (Table 1).

Table 1. Dispersive surface energy values for two Xemilofiban polymorphs at 30°C

Hydrates and Solvates

Hydrates and solvates are a key form of crystalline pharmaceutical materials and roughly one-third of organic materials can form hydrates or solvates. Solvates are crystals consisting of different numbers of solvent molecules, whereas polymorphs represent different structures of the same molecules.

The solvation state relies on both temperature and solvent vapor pressure above the solid. The solvation state of a material may affect a number of material properties including physical and chemical stability.

In addition, different solvate forms can influence the material dissolution rate, compressibility and flowability. These factors have an impact on the complete chain of the drug development process starting from preformulation and production right up to packaging and storage.

DVS is a commonly employed method to analyze solvate formation, especially hydrates. The transformation from the unsolvated state to the solvated state is a first order phase transformation.

Both solvation-desolvation processes are thermodynamically identical whether generated from the liquid or vapor phase. If both processes are carried out under equilibrium conditions, then the solvation-desolvation transition must take place at the same solvent activities in both liquid and vapor phases.

Hence, solvate formation analyzed by vapor sorption techniques represents where similar transitions would take place in the liquid-phase. There may be a vast difference in the kinetics of these transitions between the vapor phase and the liquid phase. The stoichiometry of the solvate can be determined if we know the molecular weight of the anhydrous material (Figure 2).

Figure 2. Acetone vapor sorption (red) and desorption (blue) isotherms for carbamazepine at 25°C

Gravimetric vapor sorption techniques can also be employed to explore the impact of excipients on hydrate-anhydrate phase transformations. They can analyze the kinetics of dehydration and desolvation.

A final area of characterization in the generation of hydrates/solvates of pharmaceutical materials is the use of DVS in conjunction with in-situ vibrational spectroscopy (Figure 3).

DVS water sorption data in this region reveals the absorption of two moles of water, and the Raman spectra corroborate the transformation from the monohydrate to the tri-hydrate state.

Figure 3. Spectra of nedocromil sodium at 13% and 15% RH

Anisotropic Nature of Crystals

Crystalline materials can be energetically anisotropic, which means the surface chemistry is inhomogeneous, with different crystal planes exhibiting different chemistry. Wetting experiments on macroscopic crystals have clearly demonstrated differences in surface energy between various crystal planes of active pharmaceutical ingredients.

The characteristics of the macroscopic paracetamol single crystals grown from both methanol and acetone are in line with the data reported in the literature, with major facets of (201), (001), (011), and (110).

Further, IGC SEA studies on milled paracetamol revealed that milling preferentially exposed the (010) facet of paracetamol form I crystals, whereas for unmilled samples, the (201) facet dominated.

Table 2 shows that dispersive surface energy values for the unmilled crystals differ slightly, whereas the dispersive surface energy of the smaller, milled crystals is substantially higher.

Hence, crystalline materials need to be treated as energetically heterogeneous materials, and their surface energy may not be adequately defined by a single value. Finite concentration IGC SEA experiments enable determination of surface energy distributions, which more precisely define the anisotropic surface energy for actual materials.

Table 2. Dispersive surface energy values for unmilled and milled paracetamol crystals grown from acetone solution at different particle size fractions

Crystalline Defects

Crystalline materials are seldom perfect, and even the structure of single crystals contains kinks, vacancies, boundaries, and other defect sites. Also, varying degrees of disorder can be induced to crystalline materials by processing steps such as milling, granulation and compaction.

IGC SEA is suitable to investigate such process-induced disorder, owing to its superior sensitivity to subtle surface changes. Pharmaceutical materials turn out to be more amorphous due to increasing disorder by processing or intentional creation.

Identification of the Amorphous Phase

The differences between the amorphous and crystalline phases can be identified using IGC SEA, due to its sensitivity to the formation of amorphous materials and the ability to identify variations in surface energy for amorphous materials formed through different routes (Table 3).

Table 3. Dispersive surface energy values for amorphous lactose through different processing routes

The crystalline and amorphous phases can also be differentiated using DVS. It can be used in combination with in-situ Raman spectroscopy, as well as with near-IR spectroscopy, to differentiate the crystalline and amorphous phases.

Quantifying Amorphous Contents Below 5%

Most of the amorphous content quantification methods that use gravimetric vapor sorption techniques are based on the amorphous phase sorbing more vapor than the crystalline phase.

The surface area and vapor affinity of amorphous materials are typically higher than those of their crystalline counterparts. A calibration of known amorphous contents is critical for vapor sorption techniques.

Then, a graph of equilibrium vapor uptake at a specific vapor concentration against the known amorphous content is plotted. The resulting calibration curve allows comparison of unknown amorphous contents (Figure 4).

Figure 4. Octane vapor sorption isotherms (a.) and resulting calibration curve (b.) for lactose samples with various amorphous fractions

Glassy to Rubbery Transition

While passing through the glass transition, an amorphous material often transforms from a glassy, hard, brittle material to a less viscous, ‘rubber’ state. Moreover, the molecular mobility of amorphous compounds shifts at the glass transition.

Above the glass transition, the molecular mobility improves, as evidenced by a decline in viscosity and increasing flow properties. A temperature which often induces the transformation at a characteristic temperature or temperature range is defined as the glass transition temperature (T_g).

T_g for pharmaceutical materials can be determined using IGC SEA, which can measure T_g as a function of background relative humidity. It is possible to investigate the plasticizing effect of water by exploring glass transitions at different humidity conditions. Table 4 shows the drastic decrease in T_g with increasing humidity.

Table 4. Glass transition temperature for α-D-maltose at different relative humidity conditions as measured by IGC SEA

Moisture-induced glass transitions can also be studied using DVS. The linear ramping of the humidity surrounding an amorphous material from 0% relative humidity (RH) to a humidity above the water vapor induced glass transition will clearly show a shift in vapor sorption characteristics.

Water sorption will normally be restricted to surface adsorption below the glass transition. Bulk water absorption occurs due to increase in molecular mobility caused by the material passing through the glass transition. Hence, it is possible to use the shift in sorption characteristics as a measure of the glass transition (Figures 5 and 6).

Figure 5. Humidity ramping experiment for amorphous lactose showing humidity induced glass transition and crystallization

Figure 6. In-situ images collected on amorphous lactose at 0% (A), 50% (B), 60% (C), and 90% RH (D)

Vapor-Induced Crystallization

The vapor-induced crystallization of an amorphous material often occurs with a sharp mass loss, caused by the lower surface area, surface energy, and/or void spaces in the crystalline phase. The crystallization reaction can be monitored using this mass loss (Figure 7).

If analyses, as presented in Figure 7, are carried out at various solvent and temperature conditions, it is possible to elucidate the crystallization mechanism. As a result, it is also possible to determine crystallization behaviour over a broad range of vapor concentration and temperature conditions (Figure 8).

Figure 7. Amorphous lactose crystallization at 55% RH and 25°C

Figure 8. Humidity-induced lactose crystallization at 51% RH between 22 and 32 °C

Energetic Relaxation

Drug substances that are designed for delivery through the lung are often micronized to lower the particle size to the respirable range of less than 6 µm. As a consequence of these high-energy processes, surface morphology is changed, defect sites are increased, and crystallinity is decreased. Hence, it is paramount to gain insights into the relaxation of these high-energy sites over time under different storage/exposure conditions (Figure 9).

Figure 9. Dispersive surface energy (a.) and Guttmann Ka/Kb ratios (b.) for a milled budesonide sample measured at different storage exposures of 52% RH and 25°C

Surface Energy Heterogeneity

Most materials become energetically heterogeneous due to the anisotropic nature of crystals, defect sites, impurities, different functional groups, and varying levels of amorphous content. Hence, it is desired to quantify a distribution or range of surface energies for a given material.

Conventional IGC SEA analyses are usually conducted at infinite dilution, where only interactions with the most energetic sites are quantified. Higher vapor concentrations (finite concentration) are injected in order to incorporate lower energy sites.

Previous studies measured adsorption potential or adsorption energy distributions using IGC SEA to measure the energetic heterogeneity of solids, but these values are dependent on the probe molecules and not an independent property of the solid being analyzed.

There are new methods available that use IGC SEA to determine surface energy distributions for powders. Using these methods, dispersive surface energy profiles can now be directly measured as a function of surface coverage. Valuable data in the complex surface characterization can be obtained from the measurement of energetic heterogeneity profiles (Figure 10).

Figure 10. Dispersive surface energy profile for untreated (blue), crystalline (pink), and milled (red) lactose sample

Conclusion

Pharmaceutical materials are available in different levels of complexity ranging from well-ordered materials with a defined crystal lattice to completely amorphous materials with no long-range order.

The material’s thermodynamic instability or level of disorder will have an impact on every stage of pharmaceutical development starting from formulation to production, through to storage and stability. Hence, solid material characterization is crucial to address these challenges in order to achieve a successful pharmaceutical product development and quality by design.

DVS and IGC SEA are proven vapor sorption technique for determining a range of physico-chemical properties of materials. The examples presented in this article demonstrate the applicability of DVS and IGC SEA in the characterization of crystalline and disordered materials such as hydrates, polymorphs, amorphous materials, and defect sites. DVS and IGC SEA provide key insights for the characterization and development of solid pharmaceutical materials.

About Surface Measurement Systems Ltd

Surface Measurement Systems Ltd develops and engineers innovative experimental techniques and instrumentation for physico-chemical characterisation of complex solids. We are the world leaders in Dynamic Vapor Sorption technology and Inverse Gas Chromatography instrumentation and solutions, providing professional world-class scientific and technical support for our international customers.

Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships, provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research, science, medical devices and treatments.