Patent Description:
<NUM>-[(8aS)-<NUM>-[[(<NUM>)-<NUM>-ethoxycarbonyl-<NUM>-(<NUM>-fluoro-<NUM>-methyl-phenyl)-<NUM>-thiazol-<NUM>-yl-<NUM>,<NUM>-dihydropyrimidin-<NUM>-yl]methyl]-<NUM>-oxo-<NUM>,<NUM>,<NUM>,8a-tetrahydro-<NUM>-imidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl]-<NUM>,<NUM>-dimethyl-propanoic acid and pharmaceutical compositions comprising solid forms thereof disclosed herein, which can be used as a HBV capsid inhibitor (or HBV Core Protein Allosteric Modifier), or for the treatment or prophylaxis of a viral disease in a patient relating to HBV infection or a disease caused by HBV infection.

HBV is a species of the hepadnaviridae family of viruses. HBV is a serious public health problem worldwide, with more than <NUM> million people especially in Asia-pacific regions chronically infected by this small enveloped DNA virus. Although most individuals seem to resolve the infection following acute symptoms, <NUM>-<NUM>% of HBV patients will finally develop clinical diseases during their lifespan, most notably, hepatitis, liver cirrhosis, and hepatocellular carcinoma. Every year <NUM>,<NUM> to <NUM> million people die from the end stage of liver diseases caused by HBV infection.

HBV capsid protein plays essential roles in HBV replication. HBV has an icosahedral core comprising of <NUM> copies of the capsid (or core) protein. The predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles in the cytoplasm. This step is prerequisite for viral DNA replication. There has been a couple of capsid related anti-HBV inhibitors reported. For example, phenylpropenamide derivatives, including compounds named AT-<NUM> and AT-<NUM> (<NPL>), and a class of thiazolidin-<NUM>-ones from Valeant R&D (<CIT>), have been shown to inhibit pgRNA packaging. A recent study suggested that phenylpropenamides are, in fact, accelerators of HBV capsid assembly, and their actions result in the formation of empty capsids. These very interesting results illustrate the importance of the kinetic pathway in successful virus assembly.

Heteroaryl dihydropyrimidines or HAP, including compounds named Bay <NUM>-<NUM>, Bay <NUM>-<NUM> and Bay <NUM>-<NUM>, were discovered in a tissue culture-based screening (<NPL>). These HAP analogs act as synthetic allosteric activators and are able to induce aberrant capsid formation that leads to degradation of the core protein. HAP analogs also reorganized core protein from preassembled capsids into noncapsid polymers, presumably by interaction of HAP with dimers freed during capsid 'breathing', the transitory breaking of individual intersubunit bonds. Bay <NUM>-<NUM> was administered to HBV infected transgenic mouse or humanized mouse models and demonstrated in vivo efficacy with HBV DNA reduction (<NPL>; <NPL>). It was also shown that bis-ANS, a small molecule that acts as a molecular 'wedge' and interferes with normal capsid-protein geometry and capsid formation (<NPL>).

<NUM>-[(8aS)-<NUM>-[[(<NUM>)-<NUM>-ethoxycarbonyl-<NUM>-(<NUM>-fluoro-<NUM>-methyl-phenyl)-<NUM>-thiazol-<NUM>-yl-<NUM>,<NUM>-dihydropyrimidin-<NUM>-yl] methyl]-<NUM>-oxo-<NUM>,<NUM>,<NUM>,8a-tetrahydro-<NUM>-imidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl]-<NUM>,<NUM>-dimethyl-propanoic acid (Compound (I)) was disclosed in <CIT> as a HBV capsid inhibitor (or HBV Core Protein Allosteric Modifier).

It was found that Form D of compound (I) was physically unstable which leads to form change and makes it not suitable for further drug development. As one of the objectives of this patent, several novel solid forms were identified and characterized, showing significantly improved stability compared with Form D of compound (I). Developing novel forms of compound (I) with good processability or acceptable aqueous solubility is one of the objectives of current invention. Some novel solid forms enhance the developability of compound (I) fundamentally.

The present disclosure relates generally to the novel solid forms of compound (I) and processes to make them.

The physical stability of drug substances is an integral part of the systematic approach to the stability evaluation of pharmaceuticals due to its potential impacts on drug chemical stability performance and safety. The greater the stability is, the longer the shelf life could be. Therefore, the accelerated and long term stability testing used in this invention could be used to predict shelf lives.

Generally speaking, amorphous pharmaceuticals are markedly more soluble but less stable than their crystalline counterparts. In another embodiment, surprisingly, Form Amorphous of compound (I) significantly improved stability compared with Form D of compound (I).

In another embodiment, sodium salt Form J of compound (I) showed improved stability compared with Form D of compound (I) and improved solubility compared with some of other crystal forms of the parent compound (I). An in vivo PK study showed that Form J of compound (I) exhibited much slower absorption rate to reach Cmax. Therefore, sodium salt Form J is suitable to be formulated as sustained-release oral formulation. Although Form J converted to HCl salt immediately, its apparent solubility in FaSSIF increased with time. Therefore, sodium salt Form J could be developed as enteric release formulations to avoid conversion in SGF and achieve higher solubility in intestinal environment for better absorption.

In another embodiment, Form H of compound (I) is a mono-hydrate which showed improved stability compared with Form D of compound (I). Generally speaking, hydrated crystal forms thermodynamically show the lowest solubility in water. Form H shows unexpected higher water solubility than Form A. With acceptable solid state stability, Form H of compound (I) is more preferred with oral suspension formulation.

The present invention relates to polymorphs, salts, solvates, co-crystals or combinations thereof and methods for the synthesis and production of solid forms of <NUM>-[(8aS)-<NUM>-[[(<NUM>)-<NUM>-ethoxycarbonyl-<NUM>-(<NUM>-fluoro-<NUM>-methyl-phenyl)-<NUM>-thiazol-<NUM>-yl-<NUM>,<NUM>-dihydropyrimidin-<NUM>-yl] methyl]-<NUM>-oxo-<NUM>,<NUM>,<NUM>,8a-tetrahydro-<NUM>-imidazo[<NUM>,<NUM>-a]pyrazin-<NUM>-yl]-<NUM>,<NUM>-dimethyl-propanoic acid.

The present disclosure provides an amorphous or solid form of compound (I) or solvates or combination thereof.

Also disclosed herein is an amorphous or solid form of compound (I), wherein the solid form is Form B, Form C, Form D, Form E, Form F, Form G, Form I, Form J, Form K, Form L, Form M, Form N, Form O, Form P, Form Q, Form R, Form S, Form T, Form U, Form V, Form W, Form X, or a combination thereof.

In one aspect, the solid form of compound (I) is Form D that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form D that exhibits an X-ray powder diffraction (XRPD) pattern shown in FIG.

The present invention relates to the solid form of compound (I) which is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In a further embodiment, the solid form of compound (I) is Form A that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In a further embodiment, the solid form of compound (I) is Form A that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form Amorphous that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form B that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form B that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form C that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form C that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form E that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form E that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form F that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form F that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form G that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form G that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form J that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form J that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form J that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form J, wherein the Form J is the sodium salt of compound (I).

The present invention also relates to the solid form of compound (I) which is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In a further embodiment, the solid form of compound (I) is Form H that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In a further embodiment, the solid form of compound (I) is Form H that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form I that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form I that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form K that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form K that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form K that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form K, wherein the Form K is the hydrochloride salt of compound (I).

In one aspect, the solid form of compound (I) is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form L that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form L that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form L, wherein the Form L is the hydrochloride salt of compound (I).

In one aspect, the solid form of compound (I) is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form M that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form M that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form M, wherein the Form M is the sulfate salt of compound (I).

In one aspect, the solid form of compound (I) is Form N that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form N that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form N, wherein the Form N is the sulfate salt of compound (I).

In one aspect, the solid form of compound (I) is Form O that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form O that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form O that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form O, wherein the Form O is the besylate salt of compound (I).

In one aspect, the solid form of compound (I) is Form P that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form P that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form P, wherein the Form P is the potassium salt of compound (I).

In one aspect, the solid form of compound (I) is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form Q that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form Q, wherein the Form Q is the potassium salt of compound (I).

In one aspect, the solid form of compound (I) is Form R that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form R that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form R that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form R, wherein the Form R is the potassium salt of compound (I).

In one aspect, the solid form of compound (I) is Form S that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form S that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form S that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form S, wherein the Form S is the potassium salt of compound (I).

In one aspect, the solid form of compound (I) is Form T that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form T that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form T, wherein the Form T is the calcium salt of compound (I).

In one aspect, the solid form of compound (I) is Form U that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form U that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form U that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form U, wherein the Form U is the calcium salt of compound (I).

In one aspect, the solid form of compound (I) is Form V that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form V that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form V, wherein the Form V is the ammonium salt of compound (I).

In one aspect, the solid form of compound (I) is Form W that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form W that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form W that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form W, wherein the Form W is the ammonium salt of compound (I).

In one aspect, the solid form of compound (I) is Form X that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form X that exhibits an X-ray powder diffraction (XRPD) pattern with characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.

In one aspect, the solid form of compound (I) is Form X that exhibits an X-ray powder diffraction (XRPD) pattern shown in <FIG>.

In one aspect, the solid form of compound (I) is Form X, wherein the Form X is the ammonium salt of compound (I).

Another embodiment provided herein is a pharmaceutical composition comprising the solid forms disclosed herein and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle, or a combination thereof.

Another embodiment provided herein is the use of the solid form disclosed herein or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of a viral disease in a patient.

In another embodiment, the viral disease disclosed herein is HBV infection or a disease caused by HBV infection.

Also disclosed herein is a method for the treatment or prophylaxis of HBV infection or a disease caused by HBV infection, which method comprises administering a therapeutically effective amount of the solid form or the pharmaceutical composition disclosed herein.

The invention will be more fully understood by reference to the following examples.

HPLC condition is disclosed here in Table <NUM>.

A solution of <NUM> of compound (I) in <NUM> n-propanol was placed at room temperature and evaporated to dryness.

Solids were obtained and characterized by XRPD. The XRPD pattern of Form D of compound (I) is shown in FIG. Major peaks and their related intensities in the XRPD pattern are shown in table below.

Characterization method:
XRPD: Bruker D8 Advance diffractometer X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was <NUM> KV and tube current was <NUM> mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

A solution of <NUM> of compound (I) in <NUM> a mixture of n-propanol and <NUM>-butanol (<NUM>:<NUM>, v:v) was placed at room temperature and evaporated to dryness.

The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table <NUM> and confirmed to be Form D of compound (I).

A solution of <NUM> of compound (I) in <NUM> acetone was placed at room temperature and evaporated to dryness.

The XRPD pattern of Form A of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Kαradiation. Tube voltage was <NUM> KV and tube current was <NUM> mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

<FIG> shows the X-ray structure of Form A. The single crystal X-ray intensity data were collected at <NUM> using a Bruker SMART APEX II with Cu-K-alpha-radiation (<NUM>. Structure solution and refinement was performed using the ShelXTL software (Bruker AXS, Karlsruhe). The crystal data and structure refinement is shown in Table <NUM>.

A solution of <NUM> of compound (I) in <NUM> ethyl acetate was placed at room temperature and evaporated to dryness.

The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in Table <NUM> and confirmed to be Form A of compound (I).

A solution of <NUM> of compound (I) in <NUM> isopropyl acetate was placed at room temperature and evaporated to dryness.

A solution of <NUM> of compound (I) in <NUM> acetonitrile was placed at room temperature and evaporated to dryness.

A solution of <NUM> of compound (I) in <NUM> dichloromethane was rapidly evaporated using a rotary evaporator. The solid was dried at <NUM> overnight. The solid was analyzed by XRPD. The result is shown in <FIG>.

Characterization method:
XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was <NUM> KV and tube current was <NUM> mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

A solution of <NUM> of compound (I) in <NUM> methanol was placed at room temperature and evaporated to dryness.

The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in <FIG> and confirmed to be Form Amorphous of compound (I).

A solution of <NUM> of compound (I) in <NUM> mixture solvents of methanol and dichloromethane (<NUM>:<NUM>, v:v) was placed at room temperature and evaporated to dryness.

The solid was collected for XRPD analysis. The XRPD pattern of the solid was the same as that in <FIG>. and confirmed to be Form Amorphous of compound (I).

Approximate <NUM> of Form Amorphous of compound (I) as prepared in Example <NUM> was weighed and transferred to a glass vial. <NUM> ethanol was added to form a suspension. The vial was mounted to a shaker and kept shaking at <NUM> with <NUM> rpm for <NUM>.

The XRPD pattern of Form B of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

XRPD: Bruker D8 Advance diffractometer X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was 40KV and tube current was 40mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

Approximate <NUM> of Form Amorphous of compound (I) as prepared in Example <NUM> was weighed and transferred to a glass vial. <NUM> a mixture of ethanol and methyl cyclohexane (<NUM>:<NUM>, v:v) was added to form a suspension. The suspension was agitated for <NUM> minutes.

The solid was collected for XRPD analysis. The XRPD pattern of Form C of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

XRPD: PANalytical EMPYREAN X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was <NUM> KV and tube current was <NUM> mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

Approximate <NUM> of Form Amorphous of compound (I) as prepared in Example <NUM> was weighed and transferred to a centrifuge tube. The tube was placed inside a closed container filled with n-heptane, and let sit for <NUM>.

The solid was collected and analyzed by XRPD. The XRPD pattern of Form E of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in Table below.

XRPD: Bruker D8 Advance diffractometer X-ray powder diffractometer with Cu-Kα radiation. Tube voltage was <NUM> KV and tube current was <NUM> mA. Scan range was from <NUM> to <NUM> degree <NUM>-theta. The step size was <NUM>° at a scanning speed of <NUM>°/min.

Approximate <NUM> of Form Amorphous of compound (I) as prepared in Example <NUM> was weighed and transferred into a mortar. <NUM> n-propanol was added. The mixture was grinded mannually for <NUM> minutes.

The solid was collected for XRPD analysis. The XRPD pattern of Form F of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

Approximate <NUM> of Form A of compound (I) as prepared in Example <NUM> was weighed and transferred to a glass vial. <NUM> an ethanol/n-heptane mixture (<NUM>:<NUM>, v:v) was added and sonicated mildly to ensure complete dissolution. About <NUM> of PEG <NUM> was added. The solution was evaporated to dryness at room temperature.

The solid was collected for XRPD analysis. The XRPD pattern of Form G of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was weighed into a vial and dissolved in <NUM> ethanol. The solution was stirred for <NUM> under a <NUM> water bath. <NUM> of sodium hydroxide (<NUM> eq. ) was added into the solution and stirring was applied for <NUM>. The solution became clear, then turned cloudy, and then became jell-like. <NUM> ethanol was added and the mixture was agitated at RT until the solution became flowable. After being agitated at RT for <NUM>, the product was isolated by vacuum filtration. The wet cake was washed using a small amount of ethanol and dried at <NUM> in an air-blow oven for <NUM>.

The solid was collected for XRPD analysis. The XRPD pattern of sodium salt Form J of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<FIG> shows the X-ray structure of sodium salt Form J. The single crystal X-ray intensity data were collected at <NUM>(<NUM>) K using a Bruker SMART APEX II with Mo-K-alpha-radiation (<NUM>. Structure solution and refinement was performed using the ShelXTL software (Bruker AXS, Karlsruhe). The crystal data and structure refinement is shown in Table <NUM>.

<NUM> of sodium salt Form J of compound (I) as prepared in Example <NUM> was weighed into a vial, to which <NUM> FaSSIF solution was added to form a suspension. The obtained suspension was agitated at <NUM> for <NUM>. Then, the solid was collected by filtration and dried at <NUM> under air blowing for <NUM>. The solid was collected for XRPD analysis, DSC analysis and TGA analysis.

The XRPD pattern of Form H of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

DSC analysis: TA Q2000, <NUM>-<NUM>, heating rate <NUM>/min.

TGA analysis: TA Q5000, <NUM>-<NUM>, heating rate <NUM>/min.

DSC and TGA results shown in <FIG>. indicate Form H of compound (I) has a dehydration temperature at around <NUM>.

<NUM> of Form H of compound (I) as prepared in Example <NUM> was weighed into a variable temperature chamber. The sample was placed at <NUM> for <NUM>.

The solid was collected for XRPD analysis. The XRPD pattern of Form I of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> and <NUM> acetone was added into a vial in a <NUM> water bath, and the mixture was stirred to afford a clear solution. <NUM> concentrated hydrochloric acid (<NUM> eq. ) in <NUM> acetone was added to the solution and the solution instantly became cloudy. After being agitated at RT for <NUM>, the mixture became sticky and solidified. After addition of <NUM> acetone, the mixture became flowable. The suspension was agitated for another <NUM> at RT, the solid was collected by vacuum filtration, washed with a small amount of acetone, and dried at <NUM> in an air-blow oven for <NUM>. The solid was collected for XRPD analysis.

The XRPD pattern of hydrochloride salt Form K of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of hydrochloride salt Form K of compound (I) as prepared in Example <NUM> was placed in a high relative humidity chamber closed to <NUM>% RH at ambient temperature for <NUM> days.

The solid was collected for XRPD analysis. The XRPD pattern of hydrochloride salt Form L of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<FIG> shows the X-ray structure of hydrochloride salt Form L. The single crystal X-ray intensity data were collected at <NUM> using a Gemini with Mo-K-alpha-radiation (<NUM>. Structure solution and refinement was performed using the Olex2 software. The crystal data and structure refinement is shown in Table <NUM>.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was added into <NUM> IPA, and <NUM> of sulfuric acid (<NUM> eq. ) was added to obtain a clear solution. The solvent was evaporated to <NUM> and remaining was agitated for another <NUM>, resulting in a suspension. The solid was collected by centrifugation and dried at <NUM> in a vacuum oven for <NUM>.

The solid was collected for XRPD analysis. The XRPD pattern of sulfate Form M of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> and <NUM> IPA were added into a vial and heated to <NUM> in a water bath. The solution became clear after agitation, then was cooled to RT and became slightly cloudy. <NUM> of sulfuric acid (about <NUM> eq. ) diluted in <NUM> IPA was added, resulting in a clear solution. The solution was agitated for <NUM> at RT and then for <NUM> at <NUM>, no precipitation occurred. The solvent was evaporated to <NUM>-<NUM>, which was agitated at <NUM>. The solution became very cloudy within <NUM> and continuous agitation at <NUM> resulted in suspension (which turned to oil after exposure to air). After <NUM> IPE was added drop-wise at <NUM>, the mixture was heated to RT and agitated for <NUM>. The solid was isolated by vacuum filtration,and air-dried at RT. <NUM> of resulted solid was added into <NUM> EtOAc, which was agitated for <NUM> at RT. Solid was collected by filtration, washed with a small amount of EtOAc, and dried at <NUM> in an air-blow oven for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of sulfate Form N of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> and <NUM>. <NUM> ethyl acetate was added into a vial at <NUM>, and agitated until the solution became clear. The solution was cooled to RT and it turned slightly cloudy. <NUM> benzensulfonic acid (<NUM> eq. ) in <NUM> IPA was added to the solution, which turned clear again. The solution was stirred for <NUM> hour at RT then <NUM> hours at <NUM>, precipitations occurred. The suspension was kept stirring at RT for <NUM> days. Creamy solids were collected by filtration, and were dried at RT.

The solid was collected for XRPD analysis. The XRPD pattern of besylate Form O of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was dissolved in <NUM> MeOH. <NUM> of potassium hydroxide (<NUM> eq. ) was added into the solution, which was agitated to obtain a clear solution. After being agitated for another <NUM> hours, the solvent was then reduced to <NUM>, and agitation continued at <NUM> for another 16hours. <NUM> n-heptane was added to the solution, then a small amount of solid precipitated. The solid was collected by centrifuge, and dried at <NUM> under vacuum for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of potassium salt Form P of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was dissolved in <NUM> ethyl acetate. The solution in a vial was placed in a <NUM> water bath and agitated to ensure complete dissolution, then <NUM> of potassium phthalimide (<NUM> eq. ) was added and the solution turned slightly cloudy. The solution was stirred for <NUM> hours at RT which became significantly cloudy. The solid was collected by filtration and washed by <NUM> ethyl acetate, and dried at <NUM> in an air-blow oven for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of potassium salt Form Q of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of potassium salt Form Q of compound (I) as prepared in Example <NUM> was suspeneded in <NUM> IPAc. The suspension was stirred at RT for <NUM> days.

The solid was collected for XRPD analysis. The XRPD pattern of potassium salt Form R of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of potassium salt Form Q of compound (I) as prepared in Example <NUM> was weighed into a variable temperature chamber. The sample was placed at <NUM> for <NUM> minutes.

The solid was collected for XRPD analysis. The XRPD pattern of potassium salt Form S of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Sodium salt Form J of compound (I) as prepared in Example <NUM> was dissovled in <NUM> water at RT, to which was added <NUM> anhydrous calcium chloride (<NUM> eq. ) in <NUM> water, and an emulsion like white suspension formed. Additional <NUM> water was added and the suspension was agitated at RT for <NUM> hours. The solid was collected by centrifugation and dried for <NUM> hours at <NUM> in a vacuum oven.

The solid was collected for XRPD analysis. The XRPD pattern of calcium salt Form T of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of sodium salt Form J of compound (I) as prepared in Example <NUM> was dissolved in <NUM> water at RT with sonication. About <NUM> of anhydrous calcium chloride (<NUM> eq. ) in <NUM> water was added dropwise to the above solution, the solution instantly became cloudy. After <NUM> hour of agitation at RT, the suspension became sticky and solidified. It became flowable after addition of <NUM> water with agitation for <NUM> hours at RT, the solid was collected by filtration under vacuum, washed with a small amount of water and dried at <NUM> in an air-blow oven for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of calcium salt Form U of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was dissolved in <NUM> methanol at RT. <NUM> of ammonia solution (<NUM> eq. , <NUM>%-<NUM>%) was added to the solution, the mixture was clear but precipitation occurred after <NUM> hours of agitation. After removing all the solvents, an oil was obtained. <NUM> acetonitrile and <NUM> IPE was added to the residue, solid formed and was collected by filtration, dried in a vacuum oven for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of ammonium Salt Form V of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was dissolved in <NUM> acetonitrile at <NUM>, then the solution was cooled down to RT. <NUM> of ammonia solution (<NUM> eq. , <NUM>%-<NUM>%) to the solution and the mixture was clear, and precipitation occurred after <NUM> hours of agitation. The amount of solvent was reduced to <NUM> and agitation continued for <NUM> days at <NUM>. The solids were collected by filtration, dried in a vacuum oven for <NUM> hours.

The solid was collected for XRPD analysis.

The XRPD pattern of ammonium salt Form W of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of Form A of compound (I) as prepared in Example <NUM> was dissolved in <NUM> ACN at <NUM> and cooled to RT. <NUM> of ammonia solution (<NUM> eq. , <NUM>%-<NUM>%) was added to the solution under agitation, the solution instantly turned cloudy. The suspension was agitated for <NUM> hours at RT. The solid was collected by filtration, washed with a small amount of acetonitrile and dried in a vacuum oven for <NUM> hours.

The solid was collected for XRPD analysis. The XRPD pattern of ammonium salt Form X of compound (I) is shown in <FIG>. Major peaks and their related intensities in the XRPD pattern are shown in table below.

<NUM> of compound (I) in different solid forms were stored in a stability chamber with temperature and humidity controlled at <NUM> and <NUM> %-RH, respectively. After <NUM> month, the samples were analyzed by XRPD to check their solid form and compared with their initial solid form. According to the results shown in Table <NUM>. Form D and sodium salt Form J showed better solid form stability than the original Form D as prepared in Example <NUM>.

Apparent solubility was determined by suspending <NUM> of compound (I) in different bio-relevant media including pH buffers (<NUM>). The suspensions were equilibrated at <NUM> for <NUM> hours. The suspensions were then filtered through a <NUM> PVDF filter into a <NUM>-mL HPLC vial. The quantification of the filtrate was conducted by HPLC with reference to a standard solution. The solubility results of selected novel solid forms in this invention are shown in Table <NUM>. The novel solid forms Form H, Form J, and Form Q of this invention showed higher solubility than Form A at pH7 and pH9.

Apparent solubility in water was determined by suspending <NUM> of compound (I) in purified water. The suspensions were equilibrated at <NUM> for <NUM> hours. The suspensions were then filtered through a <NUM> PVDF filter into a <NUM>-mL HPLC vial. The quantitaion of the filtrate was conducted by HPLC with reference to a standard solution. The solids were analyzed by XRPD. The solubility study results of selected novel solid forms in this invention are shown in Table <NUM>.

Surprisingly, the monnohydrate Form H shows significant higher water solubility than the anhydrate Form A.

<NUM> of compound (I) in different solid forms were stored in a stability chamber with temperature and humidity controlled at <NUM> and <NUM> %-RH. After <NUM> month, the samples were analyzed by XRPD to check their solid form and compared with their initial solid form. Form H showed better stability than the original Form D as prepared in Example <NUM>.

Claim 1:
A solid form of compound (I),
<CHM>
or salt, solvate or combination thereof, wherein the solid form is Form A that exhibits an X-ray powder diffraction (XRPD) pattern obtained with a Cu-Kα radiation and having characteristic peaks expressed in degrees <NUM>-theta at <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>°, <NUM>°±<NUM>° and <NUM>°±<NUM>°.