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For the majority of the pharmaceutical dosage forms, the substances that are used maintain solid state under the standard storage conditions, i.e. powders. The interactions of pharmaceutical powders (active ingredient(s) and excipients) with liquids and vapors (particularly aqueous solutions and their vapors) occur almost always during the production process. From the physical point of view, the interactions among individual components may differ from the expected because chemically identical substances obtained from different producers vary very much. These differences influence either the production process and/or the pharmaceutical form properties. In order to overcome these problems it is necessary to establish a control over the physico-chemical properties of the used materials.
The aim of this work was to determine physico-chemical properties of three powder clindamycin phosphate samples (labeled as sample S1, S2 and S3) acquired through different suppliers. All the analysis were made for the purpose of establishing possible differences among the tested samples that showed variable physical stability in the solution: recrystallization of the S3 sample in the aqueous solution has been established during storage under standard conditions. On the basis of the obtained data it was possible to recognize the differences among the tested clindamycin phosphate samples and to explain the anomalous behavior of one sample.
The surface free energy components for the investigated clindamycin phosphate samples were determined using Wu and Goodvan Oss method. The investigated clindamycin phosphate samples exhibit certain differences in surface free energy values as well as in surface morphology and thermal behavior. Comparison of γ+ and γ- values leads to the conclusion that all three clindamycin phosphate samples perform as monopolar, more electron acceptors, i.e. Lewis acids. However, an important difference exists between samples S1 and S2 on one and S3 on the other side. Sample S3 exhibits stronger acidic behavior, what could be connected with its recrystallization during the storage.
The samples S1, S2 and S3 have different melting points e.g. “onset” temperatures. When the melting points move towards 200oC, the width of the “onset” temperature peak is especially important. In the case of wider peak, the potential for recrystallization seems to be higher.
According to the stated, the sample S1 would be the “sample of choice” for the formulation of the stable pharmaceutical dosage form and has not shown any recrystallization tendencies during the storage period.
Technological processes of incorporating the active pharmaceutical ingredient(s) in the appropriate pharmaceutical dosage form are often very complex, although difficulties may occur in simple processes. These difficulties could be resolved with precise scientific analysis of all processes and materials included in the production of a dosage form.
Substances used for the preparation of a pharmaceutical dosage form are, under the standard conditions of storage, in solid state, such as powders. The interactions of pharmaceutical powders (active ingredient(s) and excip-ients) with liquids and vapors (particularly aqueous solutions and their vapors) occur almost always during the production process. They depend on the physico-chemical properties of all the components in the process (1).
From the physical point of view, the interactions among individual components often differ from the expected because chemically identical substances obtained from different producers vary very much. It influences either the production process and/or pharmaceutical form. These substances may vary in the quantity of the impurities, different polymorphic modifications present, degree of crystallinity, particle size etc. This variability may cause more or less serious technological problems during the production process. To overcome these problems it is necessary to explain and control all relevant physico-chemical properties that influence the technological processes and stability of pharmaceutical form.
Attempts to characterize solid surfaces, such as powders, have been undertaken using descriptions of the particles morphology and the energetics of their surfaces (2).
Fowkes (3) pointed out the significance of differentiation for non-polar and polar components of surface free energy. He proposed that the solid surface free energy (γ) could be considered as the sum of two contributions representing dispersive (D) and polar (P) forces :
Wu’s method (4), has been frequently applied to determine the surface free energy of pharmaceutical solids (5, 6, 7). However, it has been debated whether the separation of surface free energy into polar and non-polar forces is adequate to represent practical interfacial interactions (8, 9).
Surface free energy of solids cannot be determined by direct measurement, as it is the case with liquids where the value of the surface energy is determined simply by measuring the surface tension. Therefore, for the measurement of solid surface free energy some indirect methods need to be used. These methods are based on contact angle measurement and gas adsorption.
However, an approach for determination of the surface free energy of solids was developed based on the theory of apolar and acid-base (AB) interactions by van Oss and co-workers (10,11). They described the importance of AB interactions in surface phenomena :
where YLW is the apolar (or non-polar) component of the associated Lifshitz-van der Waals (LW) interactions which encompass London dispersion forces, Debye-polarization and Keesom forces.
The YAB component results from electron-donor and electron-acceptor intermolecular interactions referred to as Lewis acid-base interactions. The most common AB interaction results from hydrogen bonding. The term YAB is further divided into two parameters :
where γ+ and γ- are the electron-acceptor and electron-donor parameters of the AB component of the surface free energy of the substance, respectively. From Eqs.  and , it is obvious that if either γ+ or γ- parameter equals zero, there is no AB component contribution to the overall surface free energy (γΓ0Γ = YLW). This approach is recognized to provide accurate and real description of solid surface free energy components (12, 13), and has been applied to a variety of interfacial systems in many areas of surface science (14, 15, 16, 17). For low energy solids (3), the Young’s equation can be written in terms of LW and AB interactions :
If we assume that contact angles θ are determined with a liquid l, of which we know the total surface tension , there are still three unknown independent variables, i.e. , Țs, Țs that can be determined by solving three equations with three unknowns (11).
This LW/AB approach, which became a standard technique in the surface chemical characterization of polymers and polar materials, was applied to many interfacial systems of pharmaceutical interest with good success (9,13).
In one of them it can be assessed indirectly from wet-tability measurements. Usually, compacted powders are prepared to give the plates with a suitable geometry. Contact angles have to be measured with several liquids to assess the surface free energy of powder (19).
Thermal analysis methods, in which a physical property, i.e. enthalpy of transitions, is measured as a function of temperature or as a function of time while the substance is subjected to a temperature program are very valuable for the study of the properties of raw materials and drug products as well (20).
The aim of this work was to determine some physico-chemical properties (i.e. surface free energy, thermal and morphological properties) of three crystalline clindamycin phosphate samples, labeled as S1 S2 and S3 obtained by different suppliers. All the analysis were made in order to establish possible differences among the tested samples that showed variable physical stability in the solution: recrystaliiza-tion of the S3 sample in the aqueous solution was established during storage under standard conditions.
Model powder was crystalline clindamycin phosphate, obtained from three different sources (labeled as S1, S2 and S3 sample). Liquids used for contact angle measurement were: bi-distilled water, glycerol, ethylenglycol (Ridel-de-Haēn, Seelze-Hanover, Germany), diiodomethane and formamide (Sigma-Aldrich, Steinheim, Germany).
Contact angle measurement and surface free energy calculation
Compacts of the powders (200 mg) were prepared in a rectangular stainless steel punch and die assembly (25x10 mm) in a Specac hydraulic press (Kent, England) with a 10 s dwell time at a pressure of 2x108 Pa. The exact perimeter of the sample plates was measured using a micrometer. The compressed plate of powder was attached to the balance loop of the microbalance in a Krüss Tensiometer K12 (Germany). The temperature of the liquid used for contact angle measurements was controlled at 20±0,5°C, by flowing water from a circulator (Haake, Germany). The test liquid was placed in a special glass dish and raised by means of a motorized platform to contact the powder plate at the speed of 1,2 mm/min. From the force measurements, the contact angle was obtained using the Krüss tensiometer software (Krüss GmbH, 1996). At least five plates of the same powder were used for measurements with each liquid. The surface free energy parameters of the investigated clindamycin phosphate samples were calculated using the advancing contact angle data of the probing liquids. The equations were solved according to Good (21) using a numerical analysis and equation handling software program (Mathematica 3.0) with a personal computer. YLW was first obtained using the diiodomethane data. Subsequently, the two simultaneous equations, defined explicitly in terms of γ+ and γ-, were solved using Newton’s method. The AB components were examined for consistency and subsequently averaged.
Samples were analyzed by differential scanning calo-rimetry and thermogravimetrical analysis. These experiments have been performed on Pyris 1, Perkin Elmer and Mettler TA 3000 System, Metler Toledo, respectively. DSC measurements were carried out under inert nitrogen atmosphere (40 ml min-1) and with heating rate of 10K min-1. TGA measurements were carried out under the heating rate of 5 K min-1.
Scanning electron microscopy (SEM)
Powder samples were analyzed by scanning electron microscopy. The particles were Au/Pd coated and deposited on a double-sided carbon tape (diameter 12 mm, Oxon, Oxford instruments, UK). Samples were scanned at a voltage of 14 kV using secondary electron technique, with magnifications of 500 x and 2000 x. SEM analyses were performed using JSM 5800-JEOL instrument.
The theory underlying the Young equation includes rigorous assumptions: the solid must be smooth, homogeneous and rigid, the solid must not be perturbed by chemical interaction or by adsorption due to a liquid phase, and there should be a unique contact angle. It is, however, well known that chemical heterogeneity and surface roughness of practical solid surfaces results in contact angle hysteresis. The advancing contact angle on a smooth but heterogeneous solid surface has been regarded as a reasonable estimation of the equilibrium contact angle that would be observed on an ideal surface composed of the low energy solids (21, 22). Contact angles were measured with five liquids on each solid. The surface tension parameters of liquids suitable for solid surface free energy calculation according to Wu approach are listed in Table 1. The surface tension parameters of liquids suitable for solid surface free energy calculation according to Good and van Oss approach are listed in Table 2. The reproducibility of contact angle measurements was in the range ±2,40. The results are listed in Table 3.
For the two components approach (Wu method), among the appropriate combinations ofliquids we decided to use water/diiodomethane, ethyleneglycol/diiodomethane, formamide/diiodomethane and glycerol/diiodomethane. Diiodomethane/ water/ethyleneglycol liquids combination was used for the three components approach (Good and van Oss method). Solid surface free energy determination according to Wu and Good-van Oss approaches was assessed and the results are listed in Tables 4 and and5.5. From the theoretical point of view the solid surface energy is not dependent on the liquids used for its calculation. In practice this is not the case. Some combinations gave no result and are not listed in Table 4 and Table 5. An equation system without solution is called ill-conditioned (22). It could result from the use of solvents whose polarities are too similar, or from the use of liquids with too low surface tension for contact angle measurements (25). Our results suggest that the examined samples exhibit certain differences in surface free energy values. Comparison of γ+and γ- values leads to the conclusion that all three clindamycin phosphate samples perform as mono-polar, however, more electron acceptors, i.e. Lewis acids.
Anyway, an important difference exists between samples S and S on one and S on the other side. S sample shows much stronger acidic behavior, which might be related to its recrystallization behavior in the aqueous solution. The investigated original samples S1, S2 and S3 as well as recrystallized S3 crystals were thermally analyzed by differential scanning calorimetry and thermogravi-metrical analysis. All of them contain some moisture that can be seen in their thermograms (Figure 1). The moisture is removed in the process of heating (Table 6) (Tonset =24,27°C). For the S1, melting point is 189,373°C. Parallel TGA experiment shows that the first peak is undoubtedly connected with the “water loss” (less than 1,4%) (Figure 2). From the detailed analysis of ther-mograms of S and S it is concluded that these two samples have different thermal properties (melting points-200,348 °C and 198,575°C for S2 and S3 respectively). The position of the “water” peak for S2 and S3 is moving towards higher temperatures, i.e. about 80°C. So, the melting peak (i.e. the “onset” temperature) is similar to S1. DSC thermograms obtained by the smaller heating rate (not shown), shows clearly the presence of additional endothermal change even before the melting process. What this change means is still not clear. It is possible that the presence of the new (crystal) phases initiate the recrystallization of the other dissolved parts of the clindamycin phosphate. The TGA experiment shows (Figure 3 and and4)4) that the appearance of additional endothermal change is not connected with the loss of the mass. That clearly shows the appearance of the new solid phase. It is possible that additional phase is represented by the mixed crystals. SEM microphotographs were analyzed and morphological differences among the investigated samples could be easily perceived visually (Figures (Figures5,5, ,6,6, ,7).7). It could be assumed that S1 is quite different from S2 and especially from S. S structure is not stratified as S and S
Based on the analysis of the obtained results we may conclude: