Polymorphism of Triamcinolone Acetonide Acetate and Its Implication

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Polymorphism of Triamcinolone Acetonide Acetate and its Implication on the Morphology Stability of Finished Drug Product Jian-Rong Wang, Bingqing Zhu, Zaiyong Zhang, Junjie Bao, Gaojin Deng, Qiaoce Ding, and Xuefeng Mei Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017 Downloaded from http://pubs.acs.org on April 28, 2017

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Crystal Growth & Design

Polymorphism of Triamcinolone Acetonide Acetate and its Implication on the Morphology Stability of Finished Drug Product Jian-Rong Wang, Bingqing Zhu, Zaiyong Zhang, Junjie Bao, Gaojin Deng, Qiaoce Ding, and Xuefeng Mei* Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

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KEYWORDS: Triamcinolone acetonide acetate, injectable suspension, polymorphism, morphological transition, physical stability. ABSTRACT: Triamcinolone acetonide acetate (TAA) is a widely applied drug for rheumatoid arthritis and for the treatment of chronic inflammatory diseases. The drug was marketed as an injectable suspension with very low aqueous solubility. It was found that significant changes in crystal form, particle size and morphology were observed during shelf-life period, which resulted in product lot failure and recall. TAA was thus an interesting subject for polymorphism screening and led to the discovery of multiple solid modifications, including three polymorphs (A, B and C) and a monohydrate (MH). These forms were fully characterized by powder X-ray diffraction, Fourier transform infrared, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy, dynamic vapor sorption, and zeta potential. Single-crystal structures of four different forms and the transformation pathways among different modifications were discussed in detail. Single-crystal-to-single-crystal transformation behaviors were also analyzed and monitored by VT-XRPD and HSM. Morphological stability, form change, and particle size in suspension were also closely monitored and the data was compared with the marketed product. It was found that crystal form selection plays a critical role in the stability of the injectable suspension products. The results indicate that form B has better physical stability in the 0.5% NaCMC aqueous suspension compared to the currently marketed form.


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INTRODUCTION Polycrystalline drugs can undergo various morphological and phase transitions during the formulation and manufacturing process.1-4 In particular, injectable suspensions have received increased attention as they provide a long acting system5 and can offer relatively sustained release when compared to an aqueous solution delivery system. These suspensions usually contain a poorly water-soluble drug in selected excipients, where characteristics of the drug—such as crystal from, particle size, and morphology—play a substantial role in the suspension formulation and associated safety in administration. Any late stage solid-state transformations can pose a serious risk to the solubility, stability, and manufacturing of the drug. Take for example the case of Ritonavir semi-solid capsules, where a second polymorph found later during development forced Abbott to recall the already released drug, costing an estimated $250m in sales in 1998 alone.6 Thus, thorough investigation of any potential solid phase transformation for a market form is essential.7-12 However, the morphological and crystalline transformation in suspension products remains largely unexplored. Hence, it is desirable to understand the solid-state behavior of active pharmaceutical ingredients (APIs) and to investigate phase transformation mechanism in suspension to judiciously select the optimal solid form for development. Drugs with long-term therapy applications are prime candidates for polymorphism investigations, as many have no solid-state chemistry recorded in detail, especially those that undergo additional and significant changes during processing. Glucocorticoid drugs are a class of steroid hormones and are widely prescribed for asthma and



connective-tissue diseases.13,14-16 Several new polymorphic modifications for these compounds, such as triamcinolone acetonide, hydrocortisone, prednisolone, and bethamethasone valerate, were recently reported by professor Näther.17-23 Triamcinolone acetonide acetate (TAA, Scheme 1), is a long-term glucocorticoid clinically prescribed for the treatment of chronic inflammatory diseases such as asthma, rheumatoid arthritis, inflammatory bowel disease and autoimmune diseases.24, 25 Especially for treatment of rheumatoid arthritis, TAA can obviously inhibit secretion of interleukin-1 and TNF-α from articular synovial tissue to reduce the proliferation of capillaries and fibroblasts.25 It belongs to a class II compound according to the Biopharmaceutics Classification System (BCS) with poor aqueous solubility (0.001 mg/mL) and high permeability (log P = 3.2).26, 27 TAA is officially listed in Chinese Pharmacopoeia as an intramuscularly injectable suspension for rheumatoid arthritis. The suspension formulation is used for sustainable release of TAA and provides a long acting system. Particle size is required to be strictly controlled in the range of 3~5 µm, as the larger particle is the primary factor of muscle ache or even tissue necrosis. However, several lots of TAA suspension products easily led to some larger particles in the process of storage. The controlled 3~5 µm particles were ripened into an unacceptable size of about 40 µm (Figure 1), which renders the lot unusable and not for consumption. There is only one crystal structure reported (form A, CSD refcode: IJUTAJ) with no further solid-state characterization data.24 Thus, it is urgent to fully insight into the solid-state of TAA and to select the superior form for drug quality control and to avoid the lot failure in its suspension products.


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O O O

O HO

O H

H F

H

O

Scheme 1. Chemical structure of TAA.

Figure 1. Large particles appeared in TAA suspension formulation (50 mg / 5 mL). This study seeks to further characterize the solid-state properties of TAA, with an emphasis in understanding how the solid-state form affects the morphology, particle size, solubility, and physical stability of its suspension products. In this report, we disclose three novel solid forms, including two new polymorphs (B and C), and one monohydrate (MH). Single-crystal X-ray diffraction was used to determine the corresponding single-crystal structures of these forms. Their properties were fully characterized by powder X-ray diffraction (PXRD), Fourier transform-infrared (FT-IR), thermal analysis (TGA and DSC), hot stage microscopy (HSM), scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and zeta potential. The interconversion pathways of these forms were discussed in detail. Furthermore, the powder dissolution and the morphological changes (including the shape and particle size) in aqueous suspensions of newly discovered pure forms (B, C and MH) were evaluated and compared with the reported form A. The results of morphological



stability tests reveal that form B is the most stable form under dispersion condition and can be a superior solid form for suspension formulation. RESULTS AND DISCUSSION Preparation of Various Forms. The marketed form of TAA (form A) was used as raw material. The crystallization of TAA resulted in the discovery of three new crystalline forms, polymorphs B and C, and a monohydrate (MH). For the three crystalline forms, the patterns generated from a simulation of the single-crystal diffraction data and acquired from PXRD analysis revealed a close match, which confirmed the formation of highly pure phases. All the peaks of four solid modifications are distinct, and are used as reference in this study (Figure 2).

Figure 2. PXRD patterns of new crystalline forms (B, C and MH) compared with reported form A. Morphology and Crystal Structure Analysis. For comparison to the optical images, morphology predictions were conducted by using the Bravais, Friedel,


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Donnay and Harker (BFDH) method in Mercury.28 The results indicate form A will grow into a block crystal with a dominant (011) face along the a axis (Figure 3a), form B will grow into a needle-like crystal with a dominant (001) face along the b axis (Figure 3b), while MH may assemble into hexagonal crystal with the largest (011) face along the a axis (Figure 2d). Meanwhile, form C preferentially forms polygonal crystals. Alongside the calculated result, the polarizing microscope images (Figure 3) affirm that the various forms have different crystal habits. The observed morphology is consistent with the calculated results. Moreover, the crystal nature of these forms was further confirmed with comprehensive investigations of their intermolecular interactions and anisotropic properties.

Figure 3. The predicted growth morphology (a)-(d) and optical images of forms A-C and MH. Form A24 was reported in the orthorhombic space group P21 with one molecule of TAA in the asymmetric unit. TAA molecules formed intermolecular through



O3-H1…O4 bonds to create an infinite one-dimensional (1D) supramolecular chain along the b axis (Figure 4). The 1D chains are parallel to adjacent ones at the bc plane (Figure 5).

Figure 4. Hydrogen bonding chains network of forms A-C.


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Figure 5. 2D crystal packing of TAA solid modifications. The crystal structure for form B was determined and refined in the monoclinic space group C2 with two molecules of TAA in the asymmetric unit (Z’ = 2) (Table 1). Two independent molecules are compared in Figure 6. Notably, the main conformational difference is located at the 17-substrated side chain. These independent molecules connect in an alternating fashion via intermolecular interactions between the hydroxyl and ketone groups, forming a 1D hydrogen bonding chain structure, O2-H2…O1’ (dO…O = 2.69 Å) and O2’-H2’…O1 (dO…O = 2.86 Å) as shown in Figure 4 and Table S1 (Supporting Information). The adjacent 1D chains are arranged in the opposite direction as seen along b axis, which was different from that of form A Compared to form A, 1D chains in form B appear to arrange in an opposing fashion



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(Figure 5). In actuality, the 1D chains are crossed and rotated clockwise about 155° compared to form A (Figure 4). Table 1. Crystallographic Data and Structure Refinement Parameters Form B

Form C

MH

Formula

C26H33FO7

C26H33FO7

C26H33FO7•H2O

Temperature (K)

100(2)

100(2)

100(2)

Crystal system

monoclinic

orthorhombic

orthorhombic

Space group

C2

P212121

P212121

a (Å)

29.447(10)

11.1071(8)

8.3587(4)

b (Å)

6.202(2)

15.9298(13)

15.2343(8)

c (Å)

29.181(10)

13.6656(11)

19.1051(11)

α (°)

90

90

90

β (°)

117.596(6)

90

90

γ (°)

90

90

90

Cell volume (Å3)

4723(3)

2417.9(3)

2432.8(2)

Z

8

4

4

DClac (g/cm3)

1.340

1.309

1.350

λ

0.71073

0.71073

0.71073

S

1.043

0.990

1.034

R1

0.100

0.056

0.031

Rint

0.095

0.108

0.030

wR2

0.212

0.073

0.073

Figure 6. Overlay of two unique molecules in the crystal structure of form B.


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Form C crystallizes in the orthorhombic and noncentrosymmetric space group P212121 with one molecule of TAA in the asymmetric unit (Z = 4) (Table 1). The molecules are connected via O2-H2…O1 (dO…O = 2.86 Å) to form a 1D hydrogen bonding chain. The 1D chains are parallel to adjacent ones at the bc plane, which is the same as that of form A (Figure 5). The adjacent 2D layers at the bc plane are arranged in the opposite direction to form 3D network, which are rotated clockwise about 180° compared to form A (Figure 4). MH is crystallized in the orthorhombic space group P212121, with one molecule of TAA and one molecule of H2O in the asymmetric unit (Z = 4) (Table 1). The crystal structure and packing motifs are significantly different from that of B or C, with the introduction of H2O molecules disrupting the hydrogen bonding interactions. The crystal structure of MH was connected with an additional H2O inserted into the O2-H2…O1 with respect to forms A-C. TAA molecules interact with H2O molecules through O2-H2…O1S (dO…O = 2.82 Å) and O1S-H2S…O1 (dO…O = 2.75 Å) to form a 1D hydrogen bonding chain (Figure 5). The hydrogen bonding chains further bridged by O1S-H1S…O5 (dO…O = 2.93 Å) as shown in Figure 7. These H2O molecules are both donor and acceptor (DDA pattern)29 in hydrogen bonds connecting TAA molecules in the 3D network.



Figure 7. 3D network for MH bridged by hydrogen bonds of H2O molecules. The chemical structure of TAA indicates that the molecule has a flexible C17 substituted side chain and can form varying crystal structures with unique conformations; the differences among these structures are highlighted in the overlay of the various conformers in Figure 8. In general, each TAA molecule is comprised of five condensed rings, which include three six-membered and two five-membered rings: ring A is nearly planar, while B and C have chair conformations; D and E are the five membered rings, and display envelope conformations. The most remarkable variation between these conformers lies in the configurations of C17 substituted side chain. Additionally, the arrangement of rings A-D also presents subtle different connecting angles.


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Figure 8. Overlay of unique molecules in crystal structure of TAA forms A (light blue), B (red and green), C (orange) and MH (blue). Spectroscopic Analysis. FT-IR spectroscopy was used to understand molecular conformation and hydrogne bonding characteristics of the various solid state polymorphs.9 In particular, FT-IR spectroscopy can distinguish polymorphs that contain N-H…O, O-H…O, or other strong hydrogen bonds.30, 31 Figure 9 depicts a comparison of TAA solid state form FT-IR spectra. The significant differences observed in the FT-IR spectra are attributed to the O−H bond vibration stretching: 3300 cm−1 for A, 3380 cm−1 for B, 3462 cm−1 for C, and 3593, 3450, 3368 cm−1 for MH. The two extra peaks of MH than other three forms in the O−H bond vibration stretching region indicates the presence of hydrogen-bonding interactions between the solvent water molecules and TAA molecules in MH. In addition, the C20=O bond stretching of MH (in the region of 1800-1650 cm−1) occurs at 1755 cm-1, while in the three anhydrous forms, the analogous signals occur at about 1750 cm-1. The fact that the stretching frequency undergoes a blue shift suggests additional hydrogen bonding interactions on the unconjugated carbonyl group (C20=O). The disparity between vibrational modes for MH and forms A-C can be attributed to their hydrogen bonding, wherein the hydrogen bonding O-H…O (Figure 7) in A-C is inserted by a H2O molecule in MH.



Figure 9. FT-IR spectra of TAA forms A-C and MH. Thermal Analysis. Figure 10 depicts a comparison of the TGA thermograms for the various TAA solid-state forms. The TGA plots for forms A-C show no weight loss before they decompose at about 280 °C, indicating that these polymorphs contain no residual solvent. Comparatively, the TGA plot for MH shows 3.5% mass loss prior to decomposition, suggesting a H2O molecule (TAA and H2O stoichiometric ratio 1:1, calculated value: 3.6%) in the form which was also confirmed by single crystal structure. DSC measurements were made on all forms (A-C and MH) to determine if any of the forms could transform into another (Figure 11). Only the metastable form C exhibits one melting endothermic peak (Tonset = 276 °C), and is devoid of any signals for dehydration or transition when it is formed by heating form A. The DSC curve for MH reveals three endothermic peaks: first, a broad one between 100 and 150 °C that corresponds to the formation of form B through the loss of H2O molecules,


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then one at Tonset = 228 °C which corresponds to the formation of form C from from B, and lastly a strong exothermic peak observed at Tonset = 276 °C corresponding to the melting of form C. Both forms A and B transformed into form C (Tonset = 210 °C for A and Tonset = 248 °C for B) followed by melting of form C at about 276 °C. This data coincides with the hot-stage microscopy observations and VT-PXRD characterization (Figure S1 and S2, Supporting Information).

Figure 10. TGA for the forms A-C and MH, indicating that MH is a monohydrate (calculated weight loss for one molecular H2O is 3.6%).



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Figure 11. DSC curves at 10 °C/min of the forms A-C and MH. Single-Crystal-to-Single-Crystal

(SCTSC)

Transformation

Analysis.

Single-crystal-to-single-crystal transformations were initially observed during hot-stage microscopy experiments, and involved form A to form C transformations. Crystals for form A were isolated by evaporating solvent from a saturated methanol solution, and were confirmed pure by single-crystal X-ray diffraction measurements. Single crystals where then heated at 5 °C/min under hot-stage microscopy, and while no significant shape change occurred over the examined temperature range, a slight change in color occurred at 220 °C (Figure 12a). After being held at this temperature for 30 min, the sample was examined again by single-crystal X-ray diffraction. The analysis revealed, alongside rapid cell determination, that the unit cell had been changed and that the sample was now in form C. Note that this is the only way single crystals suitable for structure determination of form C were obtained in our screening


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experiments. To further analyze the characteristics of the form A to form C phase transformation, variable-temperature powder X-ray diffraction (VT-PXRD) was performed, and the results are shown in Figure S1 (Supporting Information). The sample was held for 5 minutes at each temperature point. It is evident that the position of the peaks of form A remains intact over the temperature range from 25 °C to 190 °C. At 200 °C, additional peaks at 2θ = 11.7, 14.0, 15.1, 16.0, and 26.4° appeared, which were identified as the characteristic peaks of form C, indicating that the phase transformation was underway. As the temperature increased, characteristic peaks of form A at 2θ = 8.2, 10.2, 12.6, 13.8, 16.4, and 17.3° gradually weakened, while the new peaks strengthened. At 220 °C, the characteristic peaks of form A have disappeared and so far the transformation to form C has gone to completion. As shown in Figure 4, the crystal structures of the two forms are quite different: the adjacent 2D layers at the bc plane are arranged parallel in the form A, while the layers are opposite in form C. The significant change in crystal structure suggests that the mechanism of this SCTSC phase transformation process includes the nucleation and gradual growth of the daughter phase lattice.32



Figure 12. Hot-stage microscopy snapshots of the single-crystal-to-single-crystal transformation (a) from A to C and (b) from MH to B. The same HSM, VT-PXRD, and SCXRD methods were conducted on MH. Both HSM (Figure 12b) and VT-PXRD (Figure S2, Supporting Information) experiments indicated that the process of phase transformation from MH to form B belong to SCTSC transformation. The single crystal of MH was heated to 155 °C and the quality of the final crystal was still high enough for SCXRD analysis. Cell determination showed that the unit cell is the same as that of form B. Analysis of the packing similarity may shed some light on the possible molecular movements during phase transformation. Hydroxyl group of TAA is interacted with the atom O2 of conjugated carbonyl group in the process of removal of the H2O molecules by heating (Figure 13). The H2O elimination from H2O-TAA hydrogen bonding unit in MH resulted in the structural transformation from 3D hydrogen bonding network architecture to 1D interaction in form B. Further observation of the crystal structure reveals notable conformational differences concerning the dihedral angle between form B and MH of the TAA molecule. The conformation of the C17 substituted side chain and the arrangement of rings A and B also present different connecting angle (the overlay diagram is presented in Figure 8).


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Figure 13. Phase transition from MH into form B on heating. Interconversion between Different Forms of TAA. The crystallization experiments reveal that at RT, form A is the most thermodynamically stable, while forms B and C can be classified as metastable. Especially in slurry experiments at RT, forms B, C and MH were exclusively transformed into form A in many organic solvents, such as ethyl acetate, isopropanol, acetonitrile, and nitromethane. Based on the slurry experiments and DSC transformation analysis, the interconversion relationship of various solid modifications is summarized in Scheme 2, where the red arrows are representative of the SCTSC transformation processes from A to C and from MH to B, respectively.



Scheme 2. Transformation relationship of TAA solid forms. From the fact that the transitions of A to C and B to C are endothermic (Figure 11), we can clearly conclude that form C is enantiotropically related to both forms A and B, according to the Burger and Ramberger “heat of transition rule”.33 However, because the melting points and enthalpies of fusion for forms A and B cannot be measured makes it difficult to determine the relative thermodynamic relationship of A and B. It is clear that form A is the thermodynamically stable polymorph at RT or lower temperature and forms B and C are metastable. Solubility and Powder Dissolution. The solubility measurements in product condition (0.5% NaCMC aqueous solution) showed that MH is the least soluble (3.2 µg/mL for MH, 5.8 µg/mL for A, 7.4 µg/mL for B, and 9.3 µg/mL for C). PXRD analysis confirmed that there were no form transformations observed for forms A and MH throughout the solubility experiments. Samples of forms B and C were transformed into MH by slurring for 24 h (Figure S3, Supporting Information). Form A was also changed into MH if the samples were slurried for more than 3 days (Figure S4, Supporting Information). Therefore, it can be concluded that in an aqueous solution, MH is the most stable form, and that pure polymorphs A-C tend to transform into less soluble MH. Because forms B and C were easily transformed into MH in the slurry experiment, the powder dissolution rate was conducted to investigate their dissolution behavior. Figure 14 showed the dissolution profiles of TAA forms A-C and MH in deionized water with the presence of 0.5% Tween 80. The figure demonstrates that, when


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compared to MH under the same dissolution conditions, the maximum solubility value for the form C is approximately 2.5 times as large. In particular, the higher concentration can be maintained for a considerable duration of time (at least 5 h). The amount dissolved for form C seems to be reduced over time following a maximum at 15−30 min. This decrease in solubility can be attributed to a re-equilibrium between the existing form C saturated in solution and the newly formed MH, which was confirmed by PXRD analyses (Figure S5, Supporting Information). Analysis for forms A and B reveal no form transformations. The apparent solubility trend is also indicative of the relative thermodynamic stability of the three polymorphic forms (C < B < A), as the higher solubility corresponds to lower stability.

25

20

Concentration (µ µ g/mL)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Form C

15

Form B Form A MH

10

5

0 0

60

120

180

240

300

Time (min)

Figure 14. Powder dissolution profiles of TAA forms A-C and MH. Morphological Stability in Injectable Suspension. For aqueous suspensions, crystal form and particle size must be closely monitored and controlled, as changes in form or morphology are more likely to occur when compared to oil suspensions.34 During a product’s shelf life and storage, temperature variations and cycling can



cause changes in particle size, specifically Ostwald ripening, where smaller particles can aggregate into larger structures.35 Another possibility is a transformation into polymorphic or solvate form, which will likely alter the rate of dissolution. Excipients play a major role in suspension stability: addition of excipients can delay or prevent phase transformation or Ostwald ripening. For TAA suspensions, it is a common practice to add 0.5% NaCMC in the product. Morphological and particle size distribution stabilities of TAA under suspension conditions were studied by SEM, together with XPRD to monitor the solid-state form. The metastable form C was found to change to MH in two weeks when dispersed in an aqueous suspending media. While other forms remain the same solid modification throughout the experiment. Figure 14 shows the particles of forms A, B, and MH at storage times t = 0, 3 and 6 month. Crystals of form A exhibited a morphology change, where smaller particles aggregated into irregular block structures. Some MH crystals were observed according to its characteristic hexagonal morphology. And the largest particle size recorded at more than 20 um at the sixth month. Surprisingly, crystals of form B maintained their prism morphology and uniform particle size without aggregation or Ostwald ripening.


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Figure 14. SEM microphotographs of A, B and MH, for t = 0, 3 and 6 month. Another method to evaluate the solubility and stability of solid forms in suspension is to consider the Zeta potential (ζ). ζ is a parameter provides an effective way to consider particle attraction and repulsion, and in turn, the stability of TAA injectable suspension. TAA in all forms had high negative surface charge, and when put into aqueous solution, had negative zeta potential. When ordered by zeta potential (absolute value), the TAA forms follow as listed: MH (−27.4 mV) > B (−22.2 mV) > A (−19.5 mV) >



C (−11.1 mV). Particles with a higher surface charge density, and in turn a higher absolute value of zeta potential, aggregate poorly due to high electrostatic repulsion and stability. The opposite is true where particles with lower surface charge density and zeta potential can better aggregate.36 Accordingly, for the investigated three forms (A, B, and MH, Figure 14), the most thermodynamically stable polymorph A, with lowest ζ value, was observed to be obviously aggregated together with Ostwald ripening growth at 6 months. Although MH presents the highest ζ value, crystals with 3D hydrogen bonding networks are more likely to undergo Ostwald ripening growth, comparing with 2D layers of the three polymorphic forms. Form B crystals with perfect ζ value (absolute value between 20~25 mV) for suspension products, and thus maintained original morphology and uniform particle size without aggregation or Ostwald ripening. In general, particle aggregation and Ostwald ripening occur in suspensions because of inherent thermodynamic instability. Formulations are often made to optimize physical stability and functionality by utilizing the appropriate solid form and particle size. Further strategies in formulation development include controlling particle size, monitoring morphology, and preventing form transformation. Most marketed formulations prefer to use the most stable solid polymorph, as other forms can be considered metastable and ultimately transform into the stable form.37 For TAA, the commercial sample was in form A, which is the most stable polymorph at RT. In aqueous solution, MH is the most stable phase, while polymorphs A-C tend to transform into the less soluble MH. However, in this state, both form A and MH easily undergo ag-


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gregation and Ostwald ripening, respectively. Interestingly, the metastable form B can survive several years by adding 0.5% NaCMC, which increases the activation energy barrier needed to be overcome to form the less soluble MH. Therefore, needle-like crystals of form B present superior stability in 0.5% NaCMC aqueous suspensions, and seem to be a better option for TAA suspension products. CONCLUSIONS TAA solids used for long-acting and injectable suspensions were examined under storage conditions. Significant changes in crystal form and morphology was observed, including particle size and shape. Polymorphism investigation on TAA led to the discovery of three new solid modifications, including two polymorphs (B and C) and a monohydrate (MH). Form B exhibits a lower mean size (

Polymorphism of Triamcinolone Acetonide Acetate and Its Implication

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