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\def\RunningAuthor{Tazyinul Qoriah Alfauziah et al.}
\firstPage{3012}
\articleType{Original Article}
\receivedDate{17.03.2019}
\acceptedDate{25.06.2019}
\revisedDate{20.06.2019}
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\title{Better in solubility enhancement : salt or cocrystal?}
\author{Iyan~Sopyan,  
            Tazyinul~Qoriah~Alfauziah\textsuperscript{*}, 
            Dolih~Gozali~\\[5pt]{Department of Pharmaceutics and Pharmaceutical Technology\unskip, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia }}

\begin{abstract}
Nowadays, most of marketed APIs are in the salt form. But not every single API was ionizable. Thus cocrystallization technique arised to overcome the problem. The aim of this review is to compare the solubility profile of salt and cocrystal. Both salt or cocrystal were used to improve the solubility of APIs and claimed for each other, which is the most effective in solubility enhancement. The salt was sformed by ionic interaction, whilst cocrystal formed by hydrogen. Both interactions changed the interaction energy and crystal packing, thus changing the physicochemical properties of APIs. Besides, other factors affecting the solubility of the binary system were melting point, particle morphology, and solubility of coformer. The solubility comparison led to understand the underlying mechanism on solubility enhancement of salt and cocrystal itself.
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}salt,\newline cocrystal,\newline solubility,\newline crystal engineering
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Tazyinul~Qoriah~Alfauziah~\\ Phone:\ ~\\  Email:\ tazyinul12001@mail.unpad.ac.id
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\section{Introduction}
The discovery and development of drugs was a very long way process due to optimization and control of drug quality was required before being given to the patients. The quality only could be achieved by highly strict control during the manufacturing process. Therefore, the active pharmaceutical ingredients (APIs) used should be stable in every stage of manufacturing, even when being administered to patient \unskip~\citep{565897:13036983,565897:13036989}. Designing solid through manipulation of the crystal structure of APIs, or in other terms is crystal engineering, are common in the pharmaceutical industry because it would only change the physical characteristic without disturbing the pharmacological activity \unskip~\citep{565897:13036965,565897:13036967}. The addition of the second component to change physicochemical properties that mostly performed were salt formation and cocrystallization \unskip~\citep{565897:13036969,565897:13036975}.

The underlying interaction of salt was ionic interaction, while cocrystal was hydrogen bonds in the crystal structure. Both interactions changed the interaction energy and crystal packing, thus changing the physicochemical properties of APIs \unskip~\cite{565897:13036967}. The salt formation was the early crystal engineering used for a long time in the pharmaceutical industry. Thus, it has become one of an essential step in drug development. Most of APIs were having nitrogen or carboxylic acid in their functional group, therefore could be performed in salt formation \unskip~\citep{565897:13037007}. But the problem arised from the hygroscopicity of salt, because of the ionic nature of the crystal \unskip~\citep{565897:13037013,565897:13036978}. Then cocrystallization was offered to overcome the problem, which could be more stable in the room temperature, being in the crystalline form, and could be used for nonionizable APIs \unskip~\citep{565897:13037021,565897:13037024}. Both salt or cocrystal were used to improve the solubility of APIs and claimed for each other, which is the most effective in solubility enhancement. But the study that compared the solubility of salt and cocrystal of APIs was still lack. Therefore, in this review, cocrystal and salt evaluation were provided, also with each advantage. Then the solubility of cocrystal and salt also examined to evaluate which the effective one.

Salt formation of APIs was used to achieve desirable physicochemical properties. Besides solubility properties, other physicochemical properties such as stability, absorption, toxicity, and manufacturability were improved through salt formation approach \unskip~\citep{565897:13036993}. Therefore, almost half of the marketed drug was in the salt form.

Cocrystal, a dissociable API-excipients, widely used in the pharmaceutical industry to improve solubility properties of APIs. As performed to itraconazole, corystallization approach was successful in improving the solubility of itraconazole using succinic acid as the coformer whilst it was problematic when trying it by traditional salt approach. Heterosynthon formed between itraconazole, and succinic acid was COOH\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}N\ensuremath{_{atom\ }}\unskip~\citep{565897:13037004}. Change in crystal structure via cocrystallization was also used to improve mechanical properties such as tablet ability. Acetaminophen was cocrystallized with theophylline resulted in a flat layer crystal structure, thus increase its tensile strength and compressibility profile\unskip~\citep{565897:13036997}. The lower solubility of cocrystal formed also could be developed into a slow-releasing tablet. As an example, cocrystal of caffeine and gentistic acid, which slower dissolved than caffeine itself could further used as chewable tablets \unskip~\citep{565897:13036995,565897:13036971}.
    
\section{Materials and Methods}
\textbf{Cocrystal}

Based on 46 scientists perspectives in the little consensus, cocrystals was defined as solids that are crystalline single-phase materials composed of two or more different molecular or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts. Meanwhile, the definition of cocrystal based on FDA Guidance is ``crystalline materials composed of two or more different molecules, typically active pharmaceutical ingredient (API) and co-crystal formers (coformers), in the same crystal lattice". Thus cocrystal belongs to multicomponent crystal sub-class, which coformer and APIs are interacted through hydrogen bond in the crystal lattice and resulting in unexpected physicochemical properties \unskip~\citep{565897:13036977}. According to the nature of the coformers, cocrystals classified into ionic and molecular cocrystals. Cocrystallization is one of the common crystal engineering approaches to overcome the solubility problem of active pharmaceutical ingredients (APIs) \unskip~\citep{565897:13037023}. Therefore, researches in cocrystals are attractive since it could be improved physicochemical properties of drugs, i.e. solubility, mechanical properties, physical stability, and bioavailability \unskip~\citep{565897:13037026}.

\textbf{H\textbf{istory of cocrystal}}

Almarsson and Zawarotko was pioneered the novel classification of pharmaceutical cocrystal as part of crystalline materials formally in their article \unskip~\citep{565897:13036970}. After 75 years of the first isolation of cocrystal (Figure~\ref{f-3d851618d88d}), Hoffman-La-Roche made the first drug-drug cocrystal, i.e. pyrithyodione and propyphenazone in 1937\unskip~\citep{565897:13036977}. In 2003, a letter by Desiraju became controversial because of his explanation about cocrystal, i.e. "a multi-component system held together by non-covalent interactions" \unskip~\citep{565897:13036986}. Then Dunitz replied that the term was also including amorphous solids, encapsulated compounds or solid solutions \unskip~\citep{565897:13036988}. But in 2005, Aakeroy and Salmon proposed three criteria for cocrystals \unskip~\citep{565897:13036966} :


  
  \begin{enumerate}
  \item \relax The starting components should be neutral
  \item \relax The starting components should be in the solid phase at ambient conditions, and
  \item \relax The starting components were crystalline and combined based on stoichiometry ratio
  \end{enumerate}
  
\bgroup
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\centering \makeatletter\IfFileExists{images/4c3564b5-68de-4b90-a419-227244daa5da-upicture1.png}{\includegraphics{images/4c3564b5-68de-4b90-a419-227244daa5da-upicture1.png}}{}
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\caption{\boldmath {Cocrystal milestones }}
\label{f-3d851618d88d}
\end{figure*}
\egroup

\begin{table*}[!htbp]
\caption{\boldmath {Advantages of pharmaceutical salt and cocrystal} }
\label{tw-aa8f2f248f83}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{LL}
\tbltoprule \rowcolor{kwdboxcolor}Pharmaceutical salt &
  Pharmaceutical cocrystal\\
\tblmidrule 
-Abundant safe counter ion are available &
  -Easily predicted via in silico simulation\unskip~\citep{565897:13037023}\\
-Most of the salt were in crystalline form &
  -Solvate formation was less occurred \unskip~\citep{565897:13037023}\\
-Could be predicted easily by pKa difference \mbox{}\protect\newline  &
  -Abundant safe coformers are available\unskip~\citep{565897:13036981} \mbox{}\protect\newline -There was no impact to safety or pharmacological effect\unskip~\citep{565897:13036981} \mbox{}\protect\newline -Present in stable crystalline form \mbox{}\protect\newline -Can be made for non-ionizable APIs compound \mbox{}\protect\newline -There was no common-ion effect\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
\textbf{E\textbf{valuation of cocrystal }}

\textbf{Mechanical properties}

Mechanical property is directly impacted by alteration of crystal lattice but relatively poorly studied. However, this property is important for manufacturing processes, especially in solid dosage forms such as milling and compaction \unskip~\citep{565897:13036994}. The research interest of crystal mechanical properties firstly growing when the tensile strength of the tablet has a linear correlation with the L-lysine salt melting point \unskip~\citep{565897:13037023}. Generally, the higher plasticity of the crystal, the better tablet ability showed by active pharmaceutical ingredients. As expected with the bonding area and bonding strength (BABS) model that the size of bonding area formation was proportional into tablet ability performance \unskip~\citep{565897:13036977,565897:13036996}. According to this model, the stronger bond between compounds indicated by a higher melting point, the tablet ability would be better \unskip~\citep{565897:13037001,565897:13037023}. By definition, tablet ability is the capacity of the powder material to be transformed into a tablet at a specified strength \unskip~\citep{565897:13036994}. In addition, plasticity affected powder tablet ability directly because it described material ability to go through irreversible deformation after given a pressure \unskip~\citep{565897:13036981}.

Flat layers composed of hydrogen bonding in the crystal system indicated the good tablet ability \unskip~\citep{565897:13037019}. The layers act as slip planes in order to improve plasticity, thus enhancing powder compaction. The presence of slip planes was the reason of tablet ability improvement as showed in \unskip~\citep{565897:13036990}. Study, which crystals with slip planes (ethyl, propyl, and butyl parabens) have superior tablet ability compared to methyl paraben, a crystal without slip planes \unskip~\citep{565897:13036990}. In addition, the existence of slip planes could also be used as the guidance in the screening process of cocrystals exhibited better mechanical properties \unskip~\citep{565897:13037018}.

Formation of caffeine and methyl gallate cocrystal (1:1) resulted in the enhancement of its powder compaction properties. Methyl gallate has an extremely poor compaction properties thus its tensile strength could not be measured. However, the elastic recovery was very high, i.e. up to 32\% at 420 MPa. Form II caffeine has a unique characteristic of tablet ability properties. It has good tablet ability in the low pressure ({\textless}150 MPa), but when the pressure increased more than 180 MPa, a significant reduction of tablet ability properties was observed. Fortunately, caffeine and methyl gallate cocrystal exhibited superior tablet ability at all the entire pressure range, which involves the presence of slip planes in its crystal structure \unskip~\citep{565897:13037018}.

Resveratrol tablet has poor compaction property at all pressure range, but in contrast, its cocrystals have better compaction property. \unskip~\citep{565897:13036994}. were using isonicotinamide, nicotinamide, and L-proline as the coformers of resveratrol, but the highest tensile strength of cocrystal was made by isonicotinamide. However, all of the resveratrol cocrystals in their study were absent of slip planes; thus, it was concluded that the tablet ability property of resveratrol dominated by its compatibility \unskip~\citep{565897:13036994}. Cocrystallization of theophylline and methyl gallate (1:1) was performed by \unskip~\citep{565897:13036981}. To evaluate the tableting performance of theophylline cocrystal. They found that cocrystallization could enhance tablet ability of methyl gallate but in contrast, reduce the tableting performance of theophylline \unskip~\citep{565897:13036981}. Generally, smaller particles of plastic materials would perform the higher compactibility because the availability of bonding area for compression was higher \unskip~\citep{565897:13037016}. 

But it was an exclusion for theophylline which has the largest particle size compared to cocrystal and methyl gallate because its compaction properties was the best one. It was concluded that the difference of their mechanical properties caused by the different crystal packing. Both of three-dimensional hydrogen bond network of methyl gallate and two-dimensional flat slip planes hydrogen-bonding of cocrystal resulted in lower plasticity compared to theophylline slip layers that consisted of hydrogen bond columns\unskip~\citep{565897:13036981}. Their study showed that cocrystallization can also deteriorate tablet ability of active pharmaceutical ingredients. 

\textbf{Solubility and dissolution}

The main physicochemical properties targeted in crystal engineering is solubility \unskip~\citep{565897:13036964}. Solubility is a function of the crystal lattice and solvation interactions and indirectly correlate to the enthalpy of fusion and melting point \unskip~\citep{565897:13036976}. The underlying mechanisms of solubility enhancement through cocrystallization are lattice energy reduction of cocrystal and better hydrophilicity of coformers. Thus, coformers can be one of the consideration factors in preparing cocrystals \unskip~\citep{565897:13037020,565897:13036984}. 

Crystal lattice would control the solubility of APIs in the solvents by giving solvation resistance. However, solvation could be a decisive role on cocrystal solubility due to hydrophobicity. In addition, coformer solubility played a role in increasing cocrystal solubility as a result of solvation barrier reduction and also correlated with dissolution rate of cocrystal \unskip~\cite{565897:13036982,565897:13037020}. Cocrystallization may either increase or decrease the solubility of the poor soluble drug. Cocrystal of fluoxetine HCl decreased using benzoic acid as the coformer, but in contrast, its solubility increased using succinic acid and fumaric acid as coformer \unskip~\citep{565897:13036982}. According to \unskip~\citep{565897:13036992} the impact of solubility coformer in cocrystal system was comparable only if they have similar molecular packing and hydrogen bonding \unskip~\citep{565897:13036992}.

There were 3 steps in the solubilization process:


  
  \begin{enumerate}
  \item \relax Breaking intermolecular bonds in the solid (solute-solute). The interaction forces must be overcome for the solute to dissolve
  \item \relax Breaking intermolecular bonds in the solvent (solvent-solvent)
  \item \relax Forming solvent-solute bonds. If the solvent-solute interactions match the solvent-solvent interactions, the driving force of solubilization is lattice energy or melting of the solid
  \end{enumerate}
  Simvastatin is HMG-Co A reductase inhibitor which becomes the first-line therapy in hypercholesteromia patients. Because of its low solubility profile (30 mg/ml) and low bioavailability (5\%), \unskip~\citep{565897:13037011}. cocrystallized simvastatin with various coformer, i.e. nicotinamide, saccharin, and malic acid. Its cocrystal using nicotinamide exhibited solubility and dissolution improvement up to 3-fold and 4-fold, respectively \unskip~\citep{565897:13037011}. Simvastatin-malic acid cocrystal also showed solubility and dissolution enhancement about 2-fold than pure simvastatin \unskip~\citep{565897:13037010}. The highest solubility enhancement was on simvastatin and saccharin cocrystal, i.e. 10-fold than its pure simvastatin \unskip~\citep{565897:13037012}. Besides the formation of hydrogen bond, it was assumed that cocrystal exhibited the higher intensity of solvent affinity and lower lattice energy of cocrystal \unskip~\citep{565897:13037010}.

Acyclovir, antiviral agent for herpes simplex, shingles, and varicella, existed in hydrate form of commercialized products. Belongs to the Class IV drugs based on BCS, Sarkar and Rohani cocrystallized acyclovir with fumaric acid, malonic acid, and tartaric acid. Heterodimer synthon was predicted to form between O-H\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}N and C-O\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}H of acyclovir and dicarboxylic acids. The solubility of acyclovir-fumaric acid and acyclovir-malonic acid cocrystal increased and were better than acyclovir-tartaric acid. Based on each cocrystal stability, acyclovir-tartaric acid cocrystal was the least stable cocrystal for both physical stability and solution stability. Acidity was become one of the problems affecting cocrystal stability as tartaric acid was the weakest acid among another coformer. The strength of hydrogen bond also highlighted by Sarkar and Rohani as the driving force for cocrystal stability \unskip~\citep{565897:13037006}.

In addition, commercial (hydrate) and anhydrate acyclovir were fast in rehydrate into dihydrated form at all RH condition, but its cocrystals were stable in all conditions except for acyclovir-tartaric acid cocrystal. 

\textbf{Melting point}

Melting point is one of important thermal behaviour that could determine the physical stability of drugs and lead manufacturer decision in choosing appropriate manufacturing route.

Generally, the cocrystal melting point would fall between the starting components (51\%). But it was also possible for cocrystal to have lower (39\%) or even higher (6\%) than its starting components \unskip~\citep{565897:13037008,565897:13036975}. Melting point also correlated with solubility with a correlation coefficient of 0.78, as shown in Stanton and Bak\textit{\space } study \unskip~\citep{565897:13037014}. However, it was a poor parameter to predict aqueous solubility of cocrystal \unskip~\citep{565897:13037020}.

\textbf{Stability}

The stability differences between APIs and its cocrystal might be caused by its different crystal packing. Generally, the chemical stability of APIs increased by cocrystallization. As shown in nitrofurantoin, cocrystal with 4-hydroxybenzoic acid was more resistant in elevated RH and temperature or even in UV exposure \unskip~\citep{565897:13037022,565897:13037017}. Dapagliflozin belongs to selective sodium-glucose cotransporter-2 (SGLT-2) and used in type 2 diabetes treatment. Its highly hygroscopic nature was the big hurdle in dapagliflozin pharmaceutical production, which water uptakes was 7.4\% at 95\% RH. Cocrystallization of dapagliflozin and citric acid exhibited the greatest resistance to moisture sorption, thus make it non-hygroscopic form. In addition, the accelerated stability performed to cocrystal showed that dapagliflozin-citric acid cocrystal was stable physically than its solvate form, which transformed into amorphous form within 3 months\unskip~\citep{565897:13036985}.

\textbf{Permeability}

Solubility enhancement of APIs through cocrystallization was expected to affect its oral absorption. Once the drug was ready to cross the membrane, drug permeability which lipophilicity was depend on was take a main role into bioavailability. However, the drug flux is proportional to its concentration gradient. Thus solubility affected permeability in advance\unskip~\citep{565897:13036991}.

Hydrochlorothiazide is a diuretic, usually used in hypertension therapy, belong to BCS class III drug, which solubility was 0.7 g/L and log P was {\textendash} 0.07. \unskip~\citep{565897:13036991}\textit{. } Studied hydrochlorothiazide cocrystals with piperazine, tetramethylpyrazine, picolinamide, malonamide, isonicotinic acid, and isoniazid. Its piperazine and picolinamide cocrystal have superior solubility (7-fold and 1.04-fold, respectively) and permeability properties compared to hydrochlorothiazide alone.


\begingroup
\makeatletter\if@twocolumn\@ifundefined{theposttbl}{\gdef\TwoColDocument{true}\onecolumn\onecolumn}{}\fi\makeatother \setlength\LTcapwidth{\textwidth}
\begin{longtable}{p{\dimexpr.04700000000000002\linewidth-2\tabcolsep}p{\dimexpr.12719999999999999\linewidth-2\tabcolsep}p{\dimexpr.16499999999999996\linewidth-2\tabcolsep}p{\dimexpr.22130000000000003\linewidth-2\tabcolsep}p{\dimexpr.3253\linewidth-2\tabcolsep}p{\dimexpr.11419999999999998\linewidth-2\tabcolsep}}
\caption{\boldmath {Solubility and dissolution profile of salt and cocrystal} }
\label{tw-50205c2ae813}
\def\arraystretch{1.1}\\\endfirsthead \hline \noalign{\vskip3pt} \noalign{\textit{Table \thetable\ continued}} \noalign{\vskip3pt} \hline \endhead \hline \noalign{\vskip3pt} \noalign{\textit{\hfill Continued on next page}} \noalign{\vskip3pt} \endfoot \endlastfoot 
\tbltoprule \rowcolor{kwdboxcolor}No & API & Salt former & Cocrystal former & Solubility and dissolution profile & Ref.\\
\tblmidrule 
1 &
  Tenoxicam  \mbox{}\protect\newline Solubility 14 mg/L &
  -Piperazine  \mbox{}\protect\newline -HCl \mbox{}\protect\newline -Methanesulfonic acid &
  -Benzoic acid \mbox{}\protect\newline -Salicylic acid \mbox{}\protect\newline -Catechol \mbox{}\protect\newline -Resorcinol (1:1) \mbox{}\protect\newline -Pyrogallol (1:1) &
  The best solubility was performed by resorcinol (10.1-fold) and pyrogallol (7.5-fold) cocrystal and piperazine (5.5-fold). It was indicated that solubility of coformer has good correlation with cocrystal solubility. Resorcinol cocrystal and piperazine salt were stable in pH 7 buffer medium up to 24 hours but pyrogallol cocrystal was partially converted into tenoxicam. However, in pH 1.2 buffer medium resorcinol cocrystal was still remain stable but pyrogallol cocrystal and piperazine salt gradually converted into tenoxicam. Resorcinol cocrystal also showed a better dissolution rate among another solid forms. &
  \unskip~\citep{565897:13036978}\\
 &
   &
   &
   &
   &
  \\
2 &
  Furosemide \mbox{}\protect\newline Solubility 7.8 mg/dL at pH 7.4 &
  Piperazine &
  -Tetramethylpyrazine \mbox{}\protect\newline -Anthranilamide  \mbox{}\protect\newline -Toluamide-ethanol \mbox{}\protect\newline -Picolinamide &
  Cocrystallization and salt formation approach were destined to modify O-H\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}O acid\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}acid and N-H\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}O sulfonamide dimer synthons and chains. \mbox{}\protect\newline Salt was formed between furosemide and piperazine. The best equimolar ratio in solubility enhancement was 1:1, which three-fold higher than 2:1. In addition, cocrystal of picolinamide also performed higher solubility, but thermodynamically metastable form thus after an hour solubility evaluation, the cocorystal has been dissociated. &
  \unskip~\citep{565897:13036973}\\
 &
   &
   &
   &
   &
  \\
3 &
  Sildenafil  \mbox{}\protect\newline Solubility 34.5 g/L &
  -Oxalic acid \mbox{}\protect\newline -Fumaric acid \mbox{}\protect\newline -Succinic acid \mbox{}\protect\newline -Glutaric acid &
  -Adipic acid \mbox{}\protect\newline -Pimelic acid \mbox{}\protect\newline -Suberic acid \mbox{}\protect\newline -Sebacic acid &
  Sildenafil glutarate exhibited the highest solubility among others form, about 73.7 g/L at 24 h. Meanwhile, pimelic acid was the highly soluble cocrystal form, about 128 g/L at 2 h. Among other compounds, glutarate and pimelic was the most soluble counterparts. Solubility enhancement by glutaric acid was caused by change in enthalpy and entropy. Glutaric acid, which more soluble than sildenafil, dissolved first then sildenafil transformed into amorphous phase. &
  \unskip~\citep{565897:13037005}\\
 &
   &
   &
   &
   &
  \\
4 &
  Etravirine  \mbox{}\protect\newline Solubility 74 mg/L at 1 h of dissolution &
  -Hydrochloride \mbox{}\protect\newline -Besylate \mbox{}\protect\newline -Tosylate \mbox{}\protect\newline -Mesylate \mbox{}\protect\newline -Sulfate &
  -Adipic acid \mbox{}\protect\newline -Benzenetricarboxylic acid &
  Etravirine was tend to form solvate/hydrate and salt, because of imbalance in hydrogen acceptor and donor numbers. Benzenetricarboxylic acid gave solubility of etravirine cocrystal five times higher at 1 h than the pure form. it was also stable after 24 h, due to the better density based on single crystal data. Compared to the salt former which formed an incongruent system with etravirine, benzenetricarboxylic acid formed a congruent system thus exhibited better stability in the solvent. Meanwhile, crystal packing of benzenetricarboxylic acid showed that API was surrounded by coformer, therefore the solubility of etravirine improved. &
  \unskip~\citep{565897:13037002}\\
 &
   &
   &
   &
   &
  \\
5 &
  Gabapentin  &
  -Salicylic acid \mbox{}\protect\newline -1-hydroxy-2-naphtoic acid \mbox{}\protect\newline -RS-mandelic acid &
  3-hydroxybenzoic acid &
  Gabapentin interacted with all tested compound through carboxyl\ensuremath{\cdot}\ensuremath{\cdot}\ensuremath{\cdot}carboxylate synthon II. All multicomponent crystal were stable thermodynamically. Solubility of 3-hydroxybenzoic acid cocrystal was pH-dependent, stable at pH 4.0 and 5.7 and less stable at pH 2.6, which means that cocrystal more soluble at pH 2.6 &
  \unskip~\citep{565897:13037003}\\
 &
   &
   &
   &
   &
  \\
6 &
  Clotrimazole \mbox{}\protect\newline Solubility 0.49 mg/mL  &
  -2,5-dihydroxy \mbox{}\protect\newline benzoic acid \mbox{}\protect\newline -2,4,6-trihydroxy \mbox{}\protect\newline benzoic acid \mbox{}\protect\newline -P-coumaric acid \mbox{}\protect\newline -Caffeic acid \mbox{}\protect\newline -Mandelic acid &
  -Adipic acid \mbox{}\protect\newline -Suberic acid &
  Mandelate salt solubility was 22-fold higher than the pure drug, while adipic acid and suberic acid cocrystal solubility were only improved about 5-fold. It was correlate enough in dissolution rate for mandelate salt and suberic acid cocrystal (increased about 1.7-fold), but adipic acid cocrystal was decreased in dissolution rate. &
  \unskip~\citep{565897:13037000}\\
 &
   &
   &
   &
   &
  \\
7 &
  Norfloxacin \mbox{}\protect\newline Solubility 0.21 mg/mL &
  -Succinic acid \mbox{}\protect\newline -Malonic acid \mbox{}\protect\newline -Maleic acid &
  Isonicotinamide  &
  Solubility of norfloxacin cocrystal increased 3-fold greater than its pure form, and norfloxacin salts increased 20 {\textendash} 45-fold greater than its pure form. Maleate salt was the highest enhancement of aqueous solubility, which proton transfer performed from carboxylic acid of maleic acid to norfloxacin molecule. It was assumed that solubility enhancement of norfloxacin salts was caused by the higher ionization potential. Meanwhile, mechanism of solubility enhancement in cocrystal was caused by change in the crystal energy. &
  \unskip~\citep{565897:13036974}\\
 &
   &
   &
   &
   &
  \\
8 &
  Itraconazole \mbox{}\protect\newline Solubility 5 mg/mL &
  Hydrochloric acid &
  Malonic acid &
  Trihydrochloride salt of itraconazole exhibited the highest aqueous solubility than other forms about 13-fold, likewise its intrinsic dissolution. It was assumed that protonation of itraconazole was the cause of its dissolution and solubility enhancement. &
  \unskip~\citep{565897:13037009}\\
\tblbottomrule 
\end{longtable}
\endgroup
\makeatletter\@ifundefined{TwoColDocument}{}{\twocolumn}\makeatother 
\textbf{Characterization}

The gold standard in cocrystal characterization is single-crystal X-ray diffraction (SC-XRD) because it could determine crystal form and provide three-dimensional structure. Thus supramolecular synthon and its crystal packing could be detected. Meanwhile, confirmation of solid form in the bulk material was by powder X-ray diffraction (PXRD) which giving fingerprint diffraction pattern of the solid form, and the procedure was easier than SC-XRD. Therefore PXRD was more reasonable for the pharmaceutical industry to characterize obtained cocrystal. Rietveldt refinement methods may be used to get a three-dimensional crystal structure from PXRD \unskip~\citep{565897:13037015}.

Infrared and Raman spectroscopy could also be used to confirm the formation of hydrogen bond in cocrystal. Cocrystal spectrum from vibrational spectroscopy might be slightly different with its starting component, but still advantageous to differentiate polymorphs and cocrystals \unskip~\citep{565897:13037015}, Table~\ref{tw-aa8f2f248f83}.

\textbf{Salt }

Salt is defined in \textit{Compendium of Chemical Terminology } as a chemical compound comprising an assembly of cations and anions. Therefore, pharmaceutical salt would be consist of API (molecular, cationic or anionic) and counterion (molecular or monoatomic) that require definite stoichiometry.

Salt formation is the most common method in aqueous solubility and bioavailability improvement for the last 60 years due to the ease of synthesis and crystallization and reliability of the product.

Salt formation approach is not only performed to modify solubility and bioavailability but also physicochemical stability, manufacturability, and toxicity \unskip~\citep{565897:13036972,565897:13036979}. Ionizable groups possessed by most of APIs were the cause of salt choosing as the preference in solubility enhancement. The various salt former could be used for one API, thus affecting the solubility and dissolution rate, and also its toxicity. The three-component system involved in salt were solvent, acid, and base. In other words, salt of X compound (acid) is formed by the transfer of from X (acid) to Y (base). Based on "rule of three", a difference of pKa between API and the salt former should be at least 3 units in order to form a good salt \unskip~\citep{565897:13036972}.

\textbf{\textbf{Evaluation of pharmaceutical salt}}

\textbf{Mechanical properties}

Desloratadine benzoate, the salt form of desloratadine and benzoic acid, was exhibited better plasticity and tablet ability profile than its pure form. Desloratadine having a tendency of capping when compaction pressure was more than 250 MPa, because of elastic deformation of desloratadine. Meanwhile, its salt form could be pressurized up to 350 MPa and still formed a good tablet. Based on elastic recovery evaluation, the salt form of desloratadine was more plastic than its pure form due to lower porosity of the salt\unskip~\citep{565897:13036968}. It was predicted that the interlocked hydrogen-bonded structure of desloratadine was the cause of its low-elastic recovery profile \unskip~\citep{565897:13036980}. 

\textbf{Melting point}

Isoniazid mesylate and isoniazid oxalate exhibited better thermal stability than isoniazid. Meanwhile, isoniazid maleate was less stable thermally than its pure form. It was shown by its thermogram, which the melting point of mesylate and oxalate salts were higher than isoniazid and melting point of maleate salt was lower than isoniazid. Generally, the melting point had a negative correlation with solubility as shown in \unskip~\citep{565897:13037000}. Study that maleate salt was having the highest solubility profile with a lower melting point, while caffeate salt was having lower solubility profile with the highest melting point \unskip~\citep{565897:13037000}. But in \unskip~\citep{565897:13036987} study, thermal stability of isoniazid salts were not closely related to its solubility profile, because as shown in the solubility at pH 6.8 media, mesylate salt was the most soluble form of isoniazid salt though the melting point was classified as high among others \unskip~\citep{565897:13036987}. 

\textbf{Solubility and dissolution}

Solubility was not closely related to the crystal structure, but the value of enthalpy and entropy were important factors in solubility determination. Saccharin was used as salt former and coformer for many basic APIs, such as vincamine, buspirone, and midazolam. In \unskip~\citep{565897:13036972}, saccharin was formulated with quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, amlodipine, and piroxicam. Among those APIs, only piroxicam formed as cocrystal and others was salt. In general, the solubility of saccharinate salts of those APIs were improved markedly, but solubility enhancement of its cocrystal was not as great as its salts form did \unskip~\citep{565897:13036972}. 

Desloratadine was also exhibited salt formation with benzoic acid, which have pKa difference at 4.45. Based on its single-crystal X-ray diffraction, desloratadine benzoate having triclinical crystal system. Its solubility increased for almost fifty-fold in water and three-fold in acidic medium. The drug release in the water of desloratadine benzoate was also improved ten-fold than its pure form. These enhancements of desloratadine salt was assumed as the change of crystal structure \unskip~\citep{565897:13036968}. 

The salt of isoniazid was synthesized using oxalic, maleic, and methanesulfonic acids through solvent evaporation method. The maleate and mesylate salts showed better solubility in aqueous media about three-fold than the pure drug. The enhancement was assumed as the layered structure of the salt formed, which stabilized by hydrogen bonds\unskip~\citep{565897:13036987}. Maleate salt of clotrimazole was performed better solubility about twenty-fold and 1.7-fold higher in dissolution rate than its pure drug \unskip~\citep{565897:13037000}.

The salt formation could either increase or decrease the solubility of APIs. The more soluble salt formed are intended to use in immediate-release formulations, mean while less soluble salt formed are preferred to use in extended-release formulations \unskip~\citep{565897:13037025}. 

\textbf{\textbf{Solubility comparison of pharmaceutical salt and cocrystals}}

Factors affecting the solubility of the binary system were a melting point, particle morphology, interaction in the crystal lattice, and solubility of coformer. In the case of the salts, the longer hydrogen bond distances of API and cofomer, the higher solubility obtained. As in \unskip~\citep{565897:13036978}. Study, the salt of glutarate, fumarate, and citrate were having distance of hydrogen bond with sildenafil more than 2.57{\AA} (distance of oxalate salt), thus affected its solubility profile \unskip~\citep{565897:13037005}. While in the cocrystal, hydrogen bond distance might not affect solubility profile directly because it was supposed that interaction of coformer and API would break as contacted to solvent. Coformer solubility assumed to give more impact to the solubility of cocrystal \unskip~\citep{565897:13036998}. The more hydrophobic of coformer, the cocrystal formed was predicted to be less soluble in the water. Sebacic and suberic acid were having longer alkyl chain than pimelic acid. Thus pimelic acid cocrystal of sildenafil exhibited the highest solubility after glutarate salt \unskip~\citep{565897:13037005}. According to particle morphology, block or plate morphology was preferred than acicular, due to the surface area was higher thus affecting the dissolution rate by optimizing medium exposure to the particle \unskip~\citep{565897:13036999,565897:13037005}. Direct API-API interaction in the crystal packing would also affect the solubility of cocrystal, which the more interaction API-API observed, the less soluble API in the solvent. Meanwhile, API that surrounded by coformer with less API-API interaction would exhibit higher solubility in the solvent \unskip~\citep{565897:13037002}.

Theoretically, the large difference of pKa between API molecule and counterion on pharmaceutical salt-affected solubility properties of API better than cocrystal \unskip~\citep{565897:13037027}. It was supported by \unskip~\citep{565897:13036972}. Study, that saccharinate salts solubility was greater than its cocrystal form. The hydrogen bond of cocrystal would be a break as soon it contacted with water/solvent, and solubility of APIs were turn into its parent form \unskip~\citep{565897:13036972}. But the comparison between APIs were different, as shown in Table~\ref{tw-50205c2ae813}. 
    
\section{Conclusion}
Physicochemical properties improvement of APIs by crystal engineering was still preferred than another approach, whether through salt formation or cocrystallization. Due to differences in the interaction of salt and cocrystal, the underlying mechanism of both methods in solubility enhancement also different. Co crystal attracts the water through its high soluble coformer which surrounds the APIs, while salt ionizes APIs to increase its solubility. Therefore, the greatest solubility enhancement by salt or cocrystal was not comparable because it depends on APIs characteristics. But still, the advantages of each method could become a consideration in physicochemical properties improvement.\textbf{\space }
    

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