Strategies for Improving the Reliability of Accelerated Predictive Stability (APS) Studies

Garry Scrivens , ... Jon T. Swanson , in Accelerated Predictive Stability, 2018

3.2 Powder X-Ray Diffraction (PXRD)

Powder X-ray diffraction (PXRD) measures the diffraction pattern of crystalline material. Each API will produce a specific pattern depending on the structure of its crystal lattice. Each polymorph, salt, or cocrystalline material will have its own specific pattern. For this reason, PXRD of the API can be done in controlled environmental conditions, using hot stage and/or controlled humidity environments to simulate APS conditions in order to assess risk of any form conversions (e.g., hydration/dehydration).

Furthermore, it can be used to determine if any change in crystalline form (e.g., hydration, salt disproportionation) in the drug product has occurred during the APS study. This relies on the presence of detectable diffraction peaks of both the ingoing API form and the forms to which it may convert at the formulated levels. In addition, the API peaks must be distinguishable from any crystalline excipient peaks.

PXRD can be used as a qualitative and sometime quantitative assessment of the degree of crystallinity of the pure API. Disorder leads to peak broadening in the in the powder pattern, and eventually an amorphous "halo." This also means that conversion to amorphous phases in APS studies is not detectable by PXRD, other than by loss of the ingoing API.

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The influence of sterilization on octacalcium phosphate for clinical applications

Kieran A. Murray , ... Cathriona O'Neill , in Octacalcium Phosphate Biomaterials, 2020

4.2.5.2 X-ray diffraction

Samples for powder XRD analysis were milled for 5   min in isopropanol using the McCrone Micronizing Mill (McCrone, Westmont, IL, United States) and then measured on a Bruker D8 Advance powder diffractometer (Bruker AXS, Karlsruhe, Germany) in Bragg–Brentano geometry using digitally filtered CuKα radiation. A range from 2.0 to 80.0 degrees 2θ was scanned with a step size of 0.0122 degrees and a counting time of 0.15   s per step. The datasets were analyzed with Rietveld refinement using the software Profex [64]. Crystal-structure models were taken from Mathew et al. [17] and Sudarsanan and Young [65] for OCP and HAp, respectively. The structure model for HAp was found to be suitable to refine the diffraction-pattern HAps with a Ca:P ratio ranging from stoichiometric (Ca:P=1.67) to Ca-deficient (Ca:P=1.50). No other crystalline phases were observed.

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Solid-State Characterization and Techniques

D. Law , D. Zhou , in Developing Solid Oral Dosage Forms (Second Edition), 2017

3.4.1.2.2 Characterization of polymorphs

In the previous section on PXRD, it was discussed that polymorphism is the existence of more than one crystal packaging by the same molecule entity. Organic molecules including drugs are notorious for their formation of multiple crystalline forms. 26,27 Polymorphs can have a significant difference in solubility, stability, mechanical properties, and thermal properties and thus may impact formulation, manufacture, and performance of pharmaceutical products. Hence, agencies generally require that crystal forms of a drug substance be examined carefully against the properties that may be relevant to the dosage form design, process development, manufacturing, and in vivo performance of the product and implement appropriate controls to safeguard the identity, strength, quality, purity, and potency of the drug product.

Polymorphs represent the local minimums in the free energy landscape of the crystalline molecule. An important topic in polymorph characterization is to delineate the thermodynamic relationship among the different crystal forms. A thermodynamically more stable form is often preferred due to the less likelihood of phase transformation in general. Metastable forms could be used, and in some cases, they may be beneficial to the manufacturing process or in vivo performance. However, the incorporation of a metastable form may have significant implications to the dosage form design, manufacturing, storage, and regulatory compliance.

Two polymorphs may be thermodynamically related as enantiotropes or monotropes. In the temperature domain, an enantiotropic relationship exists if one form is more stable under one temperature range and the other more stable under another, that is, their conversion is thermodynamically reversible. On the contrary, if one polymorph is always more stable at all temperatures (below the melting temperature), they are said to be related monotropically. The relationship could also be explained in terms of the transition temperature, T t, which is the temperature where the two forms are in thermodynamic equilibrium (or change in free energy, ΔG=0). Two polymorphs are related enantiotropically if T t lies below the melting temperatures of both forms; otherwise, they are monotropically related. The free energy landscape between any two polymorphs is represented as in Fig. 2.2.

The free energy relationship between two polymorphs may be determined by DSC. Polymorphic transformation is generally a solid-state phase transition and is often accompanied by a small change in enthalpy. If the interconversion is observed between two forms reversibly (ie, during heating and reversely during cooling), then the relationship is the enantiotropic. However, a transformation may not be observed in some cases due to insufficient kinetic rate, even if the transformation is thermodynamically favorable. In other words, a thermodynamically favorable polymorphic transformation may not happen during a DSC experiment. If a polymorphic transformation does occur at temperature T obs during heating, the true transition temperature is somewhat below T obs due to the kinetic lag. The same is true during a cooling cycle.

Burger and Ramburger 28,29 formulated several rules of polymorphic relationships based on DSC data. The heat of transition rule states that two forms are related enantiotropically if an endothermic transition is observed at some temperature, and they are related monotropically if an exothermic transition is observed at some temperature. The heat of fusion rule states that if the higher melting form has the lower heat of fusion, the two forms are usually enantiotropic. Otherwise they are monotropic. The form that melts at a higher temperature is always more stable at a high temperature. These two rules are well illustrated in Fig. 2.4.

Similarly to other rules of thumb, exceptions to the Burger and Ramburger rules do occur. A more comprehensive thermodynamic treatment of the polymorphic relationships was later introduced. 30 Yu's treatment considers both the fusion data and the temperature dependence of the extrapolated free energy differences and, therefore, can resolve the misclassifications by the Burger and Ramburger rules in some exceptions.

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Drug–Excipient Interaction and Incompatibilities

Bapi Gorain , ... Rakesh K. Tekade , in Dosage Form Design Parameters, 2018

11.6.2.2 Powder X-Ray Diffraction

Among the methods for physiological characterization of solid pharmaceutical materials, PXRD plays a pivotal role. Such a nondestructive nature and preparation of a unique pattern for the crystalline phase during characterization is essential to ensure the reproducibility of the manufacturing process (Chyall and Pharma, 2012). A direct measurement of crystalline material is plotted, where X-ray diffraction intensity is plotted against diffraction angular parameter (2θ). A compatibility study report has been depicted in Fig. 11.8, where (A) represents X-ray diffractograms of ketoprofen, polyvinylpyrrolidone, and a mixture of both, and (B) represents ketoprofen, magnesium stearate, and a mixture of both (Tiţa et al., 2011). Differences in peak, i.e., disappearance or less intensified peaks, of the mixture with that of the individual components indicates the presence of interaction between the components (Tiţa et al., 2011).

Figure 11.8. (A) X-ray diffractogram of polyvinylpyrrolidone, ketoprofen, and a 1:1 blend of a simple mixture of ketoprofen and polyvinylpyrrolidone. (B) X-ray diffractogram of polyvinylpyrrolidone, ketoprofen, and a 1:1 blend of a simple mixture of ketoprofen and magnesium stearate (Tiţa et al., 2011).

A crystalline structure-solution PXRD pattern of the acetyl-YEQGL-amide molecule has also been represented in Fig. 11.9 (Fujii et al., 2011). Diffraction peaks in the PXRD pattern for crystal product are unique. Thus an absence of crystalline peak with sufficient quantity of sample clearly indicates that the material is amorphous. Therefore, PXRD plays an important role in the determination of any change in solid structure during formulation developmental stages.

Figure 11.9. Results from powder X-ray diffraction analysis of acetyl-YEQGL-amide.

(A) Le Bail refinement; (B) Rietveld refinement with the water molecule excluded from the structural model; and (C) the final Rietveld refinement with the water molecule included in the structural model. Each plot shows the experimental powder X-ray diffraction profile (red+marks), the calculated powder X-ray diffraction profile (green solid line) and the difference profile (purple, lower line). Tick marks indicate peak positions (Fujii, Young and Harris, 2011).

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Mesoporous Silica-based Nanomaterials and Biomedical Applications, Part A

Yanhang Ma , ... Osamu Terasaki , in The Enzymes, 2018

3 2d-SMCs

It is not so easy to solve a structure of SMCs solely from powder XRD data even for the relatively simple 2d-structure. This is because F B r dumps rapidly as the magnitude of K hkl increases. However, the structural features of 2d-SMCs can be easily observed by TEM images, if they are taken along the channel direction except for chiral case. The HRTEM image of FSM-16 shows highly ordered mesopores with six-fold symmetry along the channel direction, which is difficult to reconcile with the originally proposed "folded sheet" formation mechanism. However, another type of 2S-SMC KSW-2 with c2mm symmetry indicates "folded sheet" mechanism is operating as shown in Fig. 1 [2, 3]. This part may be fully discussed in another chapter "Mesoporous silica nanomaterials synthesis" by Kuroda in The Enzymes, Volume 44.

Fig. 1

Fig. 1. (A) Schematic drawing of kanemite sheet and the intercalating effect with surfactant. (B) HRTEM image of lamellar phase and (C) HRTEM image of KSW-2 with lozenge shaped channel. Structure change from lamellar phase (B) to lozenge shape (C) through reducing number of surfactant between the layers is schematically drawn in the left column.

Simple 2d-SMC is either MCM-41 or SBA-15. Both structures are well described by the pores (rather than pipes) arranged on a hexagonal lattice (Fig. 2). Supporter of pores is continuous silica wall of SMCs (flesh-color in Fig. 2), however, silica pore-surface is not smooth even in MCM-41. In the case of SBA-15, we can (i) control roughness of the surface and (ii) furthermore introduce holes in the silica wall to connect neighboring pores. These have been studied by "in situ" gas adsorption XRD experiments [4].

Fig. 2

Fig. 2. Corresponding to Eq. (7), crystal of MCM-41 or SBA-15 can be described as single pore (B( r )) is convoluted with 2d-hexagonal lattice (L( r )). The highest point group for 2d-crystal system is p6mm.

Chiral 2d-SMC is a very interesting material, however it requires more elaborated discussion which is beyond of this scope. 2d-Periodic mesoporous organosilicas [5] is another exciting SMC and this will be discussed in the chapter "Periodic mesoporous organosilica" by Inagaki in The Enzymes, Volume 44.

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Self-nanoemulsifying drug delivery systems (SNEDDS) and self-microemulsifying drug delivery systems (SMEDDS) as lipid nanocarriers for improving dissolution rate and bioavailability of poorly soluble drugs

Marko Krstić , ... Svetlana Ibrić , in Lipid Nanocarriers for Drug Targeting, 2018

12.3.6 Characterization of Solid SEDDS

Characterization of solid SEDDS includes determination of drug physical state, crystalline or amorphous (powder X-ray diffraction-PXRD, differential scanning calorimetry); identification of polymorphic transition (PXRD, Raman spectroscopy, IR spectroscopy); evaluation of interactions between formulation constituents (IR spectroscopy, DSC); and morphological evaluation (SEM). Further details of these solid state characterization methods can be found elsewhere ( Bugay, 2001; Storey and Ymen, 2011; Baghel et al., 2016; Thakral et al., 2016). Additionally, all techniques for physicochemical characterization of liquid SEDDS mentioned previously are also performed after reconstitution of solid SEDDS.

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Levels of Solid State Properties

Rahul Maheshwari , ... Rakesh K. Tekade , in Dosage Form Design Parameters, 2018

1.8 Characterization of Polymorphs

Several methods are employed to evaluate the polymorphs like thermal analysis (differential scanning calorimetry (DSC), thermogravimetric analysis (TGA)), infrared (FT-IR) spectroscopy, Raman spectroscopy, powder X-ray diffraction (XRD), single-crystal XRD, solid-state NMR, terahertz spectroscopy, optical and electron microscopy, and incoherent inelastic neutron scattering (IINS) ( Nangia and Row, 2015).

Thermal characteristics of polymorphs are significant and are generally estimated by DSC and TGA. FT-IR supports in identifying the polymorphs by providing alteration patterns in frequencies, relative intensities, band contours, and the number of bands. The difference in spectra gives an inference to the internal arrangement of crystals. Raman spectroscopy is analogous to FT-IR spectroscopy and is considered an ideal nondestructive tool for polymorphic studies (Kurouski et al., 2014).

As far as the distinction of various polymorphs and amorphous forms is considered, Raman spectroscopy offers better spectral selectivity. XRD is the most widely employed and reliable technique to identify different crystal phases through different diffraction patterns. Changes in XRD pattern, as maybe the new peak, shoulders, or a shift, provide the proof of polymorphic transitions (French, 2014). Single-crystal XRD is a nondestructive method, which reveals internal lattice data of crystalline substances, as well as the unit cell parameters like bond length, bond angle, and unit cell type. Solid-state NMR is a relatively newer, powerful tool to study crystalline polymorphs, relative crystallinity, and amorphous content of pharmaceutical mixtures (Nam et al., 2016). This technique provides information about the local structure of selected atoms/nuclei.

Terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) are the techniques based on the utilization of the spectral information obtained in the far infrared region of the electromagnetic spectrum (Sibik and Zeitler, 2016). These techniques are now being employed for the physicochemical evaluation of solid products. The spectral interpretation and the basic instrumentation are analogous to that of FT-IR and Raman spectroscopy. It gives information on low-frequency intermolecular vibrational modes, which are difficult to be assessed in Raman spectroscopy owing to the closeness of the exciting laser line. Optical and electron microscopy provides the visible differences in topography and the structure of the crystal forms (Ermolina et al., 2014).

Crystal structure prediction is a challenging task in crystallography. Computational prediction of polymorphs is many-a-times beneficial in drug designing, screening of active forms and stable polymorphs, as well as other properties including thermodynamics. Zero-order models, CCDC (Cambridge crystallographic data center), and blind tests are the recent computational techniques which are being used to predict the crystal structures (Groom and Allen, 2014). Older and newer aspirin polymorphs have been successfully predicted by these approaches, and the newer developed polymorph is relatively more stable and active than the existing one.

It is concluded that a variety of characterization techniques for polymorphs are available which have the potential to fully elucidate the structural features as well as other properties like nucleation growth, etc. The next section is written with the view to consider the major evaluation parameters for the polymorphs.

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Lipid nanoparticulate systems

Shruti U. Rawal , Mayur M. Patel , in Lipid Nanocarriers for Drug Targeting, 2018

2.6.7.3 Small angle X-ray scattering

X-ray scattering is mainly used for assisting the DSC or PCS data to confirm the drug crystallinity and stability of the nanoparticles. It involves the passage of an X-ray beam generated by synchrotron through a nanodispersion at defined angles, but doesn't record diffraction patterns, such as the PXRD method. The scattering patterns are recorded instead. The presence of peaks provides details about drug encapsulation in the crystalline or amorphous regions of the nanoparticles. Small angle X-ray scattering (SAXS) is a useful method to infer the arrangement of lipid matrix and its association/interaction with the encapsulated drug (Castro et al., 2009; De Souza et al., 2012). When combined with the DSC, this method gives us detailed information on encapsulated drug. Another method similar to this is wide angle X-ray scattering. Both these methods have a distinct advantage of analyzing the colloidal suspensions in nondiluted, native state (Svilenov and Tzachev, 2013; De Souza et al., 2012; Martins et al., 2007; Noack et al., 2012).

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API Solid-Form Screening and Selection

M.Y. Gokhale , R.V. Mantri , in Developing Solid Oral Dosage Forms (Second Edition), 2017

4.6.2 Case study 2: LY333531 145

The following case study is extracted from an excellent article by Engel et al., which reported an integrated, tiered-approach to select a salt form of a drug candidate.

LY333531 is a weakly basic drug with low solubility of the free base (<1   µg/mL). Although the pK a of the drug is not reported by the authors, it is estimated to be 9–11, based on the presence of a tertiary amine. Based on the need for oral dosage form of this BCS class II drug, the authors evaluated salt forms. They crystallized small lots (<1   g) of hydrochloride, sulfate, mesylate, succinate, tartrate, acetate, and phosphate salts. Preliminary characterization using polarizing microscopy, thermal analysis, PXRD and solubility was conducted on all seven salts. Based on the poor crystallinity, low solubility, and difficulty in chemical purification, only two salts (namely, hydrochloride and mesylate) were chosen for further consideration. The two salts, hydrochloride and mesylate, were subjected to further characterization including polymorphism, hydrate formation and hygroscopicity, stability, purification, filterability, and pharmacokinetics in dogs. Although methanol/water was initially used to prepare the mesylate salt, an alternate-solvent system using acetone/water (9:1   v/v) was chosen to avoid generation of methyl methanesulfonate, a mutagen. Three forms of hydrochloride forms with varying degrees of hydration were identified: an anhydrate form and two hydrates. The two interconverting hydrates were tentatively assigned to be monohydrate and tetrahydrate based on the vapor pressure isotherm data, although the exact structures of these hydrates were not determined. The anhydrate form did not show significant hygroscopicity (water uptake) during the vapor isotherm experiments and was considered for further stability and bioavailability assessments. Only a monohydrate form of mesylate salt was reported, and it showed no significant water uptake up to 90% RH. No change in PXRD pattern was seen at the end of the vapor isotherm experiments, although a small amount of hysteresis was seen during the desorption phase. The aqueous solubility of mesylate (0.5   mg/mL) was 5X higher than the hydrochloride salt (0.1   mg/mL). The chemical stability of the two salts as well as blends with three excipients was found to be acceptable after 1 month of storage at 40°C/75% RH and 50°C. Preliminary crystallization and filtration studies on both salts indicated that while there was no filtration advantage of one salt over the other, the purification was a lot better with the mesylate salt than the hydrochloride salt. The mesylate salt was found to be 2.6X more bioavailable compared to the hydrochloride salt when dosed as an oral suspension at 20   mg/kg in dogs. The mesylate salt monohydrate form was chosen as the API for further development.

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Profiles of Drug Substances, Excipients, and Related Methodology

Kevin Beattie , ... Jasmina Novakovic , in Profiles of Drug Substances, Excipients and Related Methodology, 2013

2.4 Crystallographic properties

2.4.1 Powder X-ray diffraction

Various polymorphic and pseudopolymorphic forms of Carvedilol have been described in literature. They include amorphous Carvedilol [9,11], crystalline Form I [5,12,13], Form II [5,12–15], Form III [12,16–19], Form IV (hemihydrate) [12,16–21], Form V (methyl ethyl ketone solvate) [12,16–19], Form VI (ethyl acetate solvate) [14], Form VII [22], and Form IX (hemihydrate) [22]. A novel crystalline form of Carvedilol identified as "potentially an ethyl acetate solvate" has also been reported in literature [23] (differing in crystalline form the previously quoted ethyl acetate quoted above). Carvedilol Form I is identified as the thermodynamically most stable crystalline form [5,13]. A summary of the characterization data associated with the X-ray diffraction of each crystal form of Carvedilol is provided in Table 4.2. Studies have also been reported that quantitatively determined, by PXRD, low amounts of amorphous Carvedilol present (i.e., as low as 1%) in the presence of crystalline Carvedilol [11].

Table 4.2. Summary of X-ray diffraction data for the crystal forms of Carvedilol

Polymorphic identity X-ray diffraction peaks reported* (2θ)° Additional data (i.e., FTIR, DSC, TGA) References
Form I 9.5, 10.8, 12.0, 14.6, 19.6, 21.5, 22.3 FTIR: 3451   cm−   1 (characteristic peak) compared to Form II (3345   cm−   1) [13]
Form II 5.8, 11.6, 13.0, 13.6, 14.8, 15.2, 16.5, 17.0, 17.5, 18.4, 19.2, 20.3, 21.0, 21.4, 21.7, 22.9, 23.5, 24.3, 25.4, 26.2, 27.5, 28.1, 29.4, 31.4, 32.5, 34.2, 35.4, 38.2, 39.3, 41.9, 44.8, 48.1 FTIR: 3345, 2061, 2997, 2836, 1630, 1608, 1591, 1504, 1455, 1444, 1403, 1348, 1334, 1305, 1286, 1253, 1215, 1178, 1156, 1120, 1101, 1042, 1023, 1002, 980, 958, 915, 871, 850, 785, 748, 728, 721, 621, 580, 465   cm−   1 [15]
Form III 8.4, 9.3, 11.6, 13.2, 13.5, 14.2, 15.3, 15.8, 17.4, 18.4, 19.4, 20.6, 21.4, 22.0, 26.5, 27.6 DSC (endothermic peak): 96–100   °C [12,17,20]
Form IV (hemihydrate) 11.9, 14.2, 15.7, 16.5, 17.7, 18.3, 19.2, 19.6, 21.7, 22.2, 23.9, 24.2, 24.9, 27.4, 28.2 DSC: (onset) 94–96   °C, (peak) 104   °C, TGA: 2% loss due to water [17,20]
Form V (MEK solvate) 4.1, 10.3, 10.7, 11.5, 12.6, 14.0, 14.8, 15.4, 16.4, 16.8, 18.8, 20.8, 21.1, 21.6 and 25.4 DSC (endothermic peaks): 67   °C, 115   °C; TGA: weight loss of 14% (consistent to a loss of one MEK molecule per one molecule of Carvedilol, followed by a recrystallization event and a melting peat at 115   °C consistent to Form II) [17]
Form VI (ethyl acetate solvate) 5.8, 6.5, 7.3, 10.7, 11.1, 11.5, 13.1, 13.7, 16.0, 16.8, 17.7, 18.5, 23.0, 30.5 DSC (endothermic peaks at 74   °C (main): 112   °C (minor))
FTIR: 613, 740, 994, 1125, 1228, 1257, 1441, 1508, 1737, 2840, 3281, 3389, 3470   cm−   1
TGA: weight loss: 13% from 35 to 104   °C		 [14]
Form VII 6.4, 6.8, 10.9, 11.6, 12.9, 13.6, 16.8, 17.5, 17.9, 23.3, 27.2 FTIR: 3469, 3278, 2871, 1124, 1096, 745, 723   cm−   1
DSC (endothermic peaks): 73   °C (Form VII to Form II transition), 114   °C (Form II melting)		 [22]
Form IX (hemihydrate) 6.2, 6.5, 11.4, 12.4, 13.6, 14.7, 16.9, 19.3, 19.6, 23.2 FTIR: 3568, 3339, 3288, 2943, 2896, 1350, 1308, 1288, 1104, 997, 737   cm−   1
DSC (endothermic peaks): 80   °C (minor; i.e., release of water from crystal lattice) and 99   °C (major)		 [22]
Potentially an ethyl acetate solvate 4.3, 8.5, 10.1, 10.6, 11.1, 12.7, 13.6, 15.6, 16.6, 17.0, 19.1, 19.9, 20.3, 21.2, 25.0, 25.4 DSC (endothermic peaks): 60 and 113.0   °C
TGA: weight loss of 40% from 25 to 60   °C		 [23]

*Note: for readability purposes, the 2θ values above are not reported with their associated ranges (i.e., typically ±   0.1 or 0.2°). Refer to the specific reference for details.

The power X-ray diffraction pattern of one of the crystalline forms of Carvedilol (i.e., Form II) is illustrated in Figure 4.1.

Figure 4.1. PXRD of Carvedilol, Form II.

2.4.2 Single crystal structure

Single crystal structure X-ray data of Carvedilol, Form II, confirms that the unit-cell dimensions are a  =   15.5414 (14)   Å, b  =   15.2050 (12)   Å, c  =   9.1174 (8)   Å, β  =   100.730 (7)°, and V  =   2116.8 (3)   Å. This is consistent with a monoclinic, P21/c space group. Although it has been shown that both Carvedilol Forms I and II are both monoclinic and crystallize in the same space group, the cell parameters are completely different (i.e., Form I: a  =   9.094 (1)   Å, b  =   12.754 (1)   Å, c  =   18.330 (2)   Å, and β  =   97.36 (1)°). Each form has two classical hydrogen bonds; that is, carbazole N-atom forms an intermolecular hydrogen bond to the 2-methoxy O atom and the hydroxyl group forms an intermolecular hydrogen bond to the amino N atom but differ significantly in the two torsion angles of the chain connecting the aromatic residues [24].

Crystal data for Carvedilol Form IV (hemihydrate) have also been reported in literature. This hemihydrate has reported unit-cell dimensions of a  =   13.517(3)   Å, b  =   16.539(3)   Å, c  =   19.184(4)   Å, β  =   94.27(3)°, and V  =   4276.9(15)   Å [20]. This solvatomorph exhibits a monoclinic, P21/n space group [21,25].

Exhaustive analysis of the Carvedilol conformations has been published. Multidimensional conformational analysis suggests a total of 177, 147 (i.e., 3   ×   1011) conformational possibilities for this drug substance. Pharmacophore fragment-based prediction and gas-phase ab initio optimization of Carvedilol conformations has also been performed to elucidate carvedilol's conformational identity [26–28].

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