Formulation Strategies to Improve the Stability and Handling of Oral Solid Dosage Forms of Highly Hygroscopic Pharmaceuticals and Nutraceuticals
2. Formulation Strategies to Reduce or Control Hygroscopicity
2.1. Film Coating
2.1.1. Aqueous Solvent Coating
Combination of Water-Soluble and Water-Insoluble Polymers
2.1.2. Organic Solvent Coating
2.1.3. Dry Powder Coating
2.2.1. Encapsulation by Spray Drying
Single Polymer as Wall Materials
Combination of Polymers as Wall Materials
2.2.2. Encapsulation by Coacervation
Double-Emulsion Complex Coacervation for Hydrophilic Bioactives
Coacervation by Gelation
2.3. Co-Processing with Excipients
2.3.1. Amorphous and Low-Crystallinity Excipients
2.3.2. Hydrophilic Excipients
2.3.3. High Tg Excipients
2.3.4. Non-Hygroscopic and Inclusion Complex-Forming Excipients
2.4. Crystal Engineering
2.4.1. Co-Crystallization by Solvent Evaporation
2.4.2. Co-Crystallization by Liquid-Assisted Grinding
2.4.3. Co-Crystallization by Solvent Evaporation and Liquid-Assisted Grinding
2.4.4. Co-Crystallization by Neat Grinding
2.4.5. Co-Crystallization by Melt Crystallization
3. Conclusions and Perspectives
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
|API-IL||Active Pharmaceutical Ingredient—Ionic Liquid|
|FDA||Food and Drug Administration|
|GRAS||Generally Recognised As Safe|
|HPMC||Hydroxypropyl Methyl Cellulose|
|LCC||Low Crystallinity Cellulose|
|PSAA||Polymeric Surface-active Agent|
|SPI||Soy Protein Isolate|
|TCM||Traditional Chinese Medicine|
|Tg||Glass transition temperature|
|THEDES||Therapeutic Deep Eutectic Solvents|
|WPC||Whey Protein Concentrate|
|WPI||Whey Protein Isolate|
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|Aqueous solvent coating|
Polyvinyl Alcohol (PVA) and mannitol (sweetener)
|At 25 °C/75%RH, moisture absorption rates increased in this order: uncoated tablets (~7%) > PVA-film-coated tablet > sugarless layer-coated tablets (0.25%). It was lowest at mannitol:PVA concentration of 15:2.5 and 15:4 (w/w).|||
|Citric acid/Sodium bicarbonate effervescent tablets||Fluid bed||Poly(vinylpyrrolidone) (PVP)||Moisture absorption rate constants (within 15 min) of coated tablets (0.34–0.50) was lower than uncoated granules (0.67) and commercial vitamin C ET (0.71), showing decreased hygroscopicity.|||
|Lactose monohydrate, microcrystalline cellulose, pre-gelatinized starch, magnesium stearate and colloidal silica||Fluid bed||Eudragit® L 30D-55|
PVA-based Opadry AMB®
HPMC-based Sepifilm™ LP 014
|Sepifilm and Opadry films were more hygroscopic than Eudragit film. Eudragit film was the most effective coating for limiting moisture sorption.|||
|Freeze-dried garlic powder||Pan-coating||Amorphous polymers:|
HPMC-based Methocel® E5
Eudragit® E PO
Presence of crystalline in polymer:
PVA-based Opadry AMB®
(Anti-plasticizing agent: PVP)
|Opadry AMB® was chosen due to its most promising moisture-protective ability at its glassy state. The addition of anti-plasticizing agent increased water uptake instead, and was deemed unsuitable to enhance the polymer’s performance.|||
|Ranitidine Hydrochloride||Pan-coating||Eudragit® E PO and Eudragit® RLPO||Eudragit RLPO 10% and Eudragit E PO 10% coated tablets absorbed less moisture at all the tested conditions.|
In 350 h at 75%RH, it absorbed 15–20% compared with uncoated tablets at 45–50%.
In 200 h at room temperature (RT), it absorbed 4–6% moisture compared with uncoated tablets at 8–10%.
In 170 h at 75%RH, it absorbed 10–15% compared with marketed formulation RANTEC 300 at 35–40%.
|Metoprolol tartrate tablets||Pan-coating||Water-insoluble Zein|
Plasticizer: PEG400 or glycerol
|Water vapor permeability of aqueous-based coating was lower than organic-based with PEG400.|||
|Calcium chloride tablets||Fluid bed||Lipophilic substance:|
Stearic acid (SA)
Water-soluble film forming polymer:
Hydroxypropyl cellulose (HPC)
Polymeric surface-active agent (PSAA)
|This combination of polymers helped to lower water permeability of the film compared to individual component films, where HPC:SA:PSAA at ratio of 62:25:10 had the lowest water vapor transmission rate at 60 g/m2 day.|
The uncoated tablets had the highest moisture absorption through the test period compared to coated tablets. HPC:SA:PSAA at ratio of 62:25:10 had the highest sealing capability, with a weight gain of only 3.5% in RT/75%RH after 168 h compared with 10% for uncoated tablets.
|Herniara glabra L. extract||Fluid bed||Lipophilic/enteric substance: Shellac|
Water-soluble film forming polymer:
Hydroxypropyl methyl cellulose (HPMC)
Stearic acid (SA), PEG1500, PEG400
Pigment: Titanium dioxide
|Combination formulation of 25% HPMC, 20% shellac, 10% PEG 1500, 29.6% PEG400, 5% tween80, 10% titanium oxide and 0.4% acid red 2 offered good protection against moisture compared with the core tablets, with its weight gain decreasing from 16.1% in core tablets to 5.7% at 75%RH, and from 18.2% to 7.5% at 90%RH after around 110 h.|
The long-term and accelerated stability studies showed stability of formulation.
|Vitamin C, E, B2, calcium pantothenate, L-cysteine||Pan-coating||Sugarless layer:|
Undercoating (UC) 2%: HPMC 10%, Purified Water (PW) 90%
Build-up coating (BC) 38%: Erythritol 18.2–22%, talc 10.6%, TiO2 0.8%, MCC 0–3.8%, powdered acacia 4.6%, PW 62%
Syrup coating (SC) 5%: Erythritol 34.2%, PEG6000 3.8%, PW 62%
Polishing: Mixture of waxes, Carnauba wax and white beeswax
|Lower hygroscopicity of the sugarless coated tablets was confirmed by the stability of the actives after storage at 40 °C/75%RH for 6 months under closed condition, where >95% drug content remained compared to <90% in sugar-coated tablets.|
Stability of the actives after storage at 40 °C/75%RH for 1 month under open conditions left >95% drug content in sugarless coated tablets, which was higher than uncoated tablets with <85% drug remaining.
The stability and therefore hygroscopicity of sugarless coated tablets were superior to uncoated tablets, and similar to sugar-coated tablets.
|Pyridostigmine Bromide||Fluid bed||Seal layer coating:|
Sustained release layer coating: Surelease®
Waterproof layer coating:
Opadry II HP
|At 25 °C/60%RH, 30 °C/65%RH and 40 °C/75%RH, the uncoated core pellets had their moisture absorption potential increased after 4 h, in contrast to the insignificant increase in moisture absorption of coated pellets up to 4 weeks. Coated pellets’ hygroscopicity was significantly less compared to pure PB which rapidly transformed from solid to liquid state within 10 min.|||
|Choline Alfoscerate||Organic solvent coating (subcoating)|
Aqueous solvent coating (outer coating)
|Hydrophobic substance: HPMC-based Opadry I®|
PVA-based Opadry AMB®
|Film-coated core tablets maintained their appearance for 30 days in 60%RH.|
Visual observation of the chosen formulation before and after 3 months exhibited no change, compared with a deformed commercial capsule that was packaged in Zymax blister film.
|Organic solvent coating|
|Aspirin (Acetylsalicylic Acid)||Pan-coating||Shellac||Shellac-coated tablets had significantly lower water uptake rates at 12.2% than HPMC-coated tablets at 19.2% at 100%RH.|
The difference was less pronounced at 75%RH with uptake rates at 3.0% compared with HPMC-coated tablets at 4.2%.
This shows that shellac had higher potential for moisture protection than HPMC especially at high RH.
However, the difference between the observed stability of drug was not as pronounced.
Much lower shellac coating levels were needed for similar moisture protection as HPMC-coated tablets.
|Solid dispersion of glimepiride and poly(ester amide) hyperbranched polymer||Pan-coating||HPMC phthalate|
Tablet core mixed with lactose (filler) and magnesium stearate (lubricant)
|After 24 h in 75%RH, the increase in weight of solid dispersion powder at 29.5% (deliquescent) was significantly larger compared with the tablet core at 3.0% (hygroscopic) and coated tablets at 1.7% (slightly hygroscopic).|||
|Diclofenac||Fluid bed||Hydrophobic substance:|
Hydrogenated Rosin (HR)
Dibutyl sebacate (DBS)
|Hydrophilic plasticizer GLY was incompatible with hydrophobic HR due to their opposing natures. Flexible films cannot be formed as they cannot blend uniformly, resulting in brittle non-uniform films.|
HR films plasticized with DBS gave
extremely low rates of water vapor transmission rates (10−5 g cm/cm2/24 h), which was very low compared with shellac.
|Dry powder coating|
|Pyridostigmine Bromide||Direct compression||Hydroxypropyl methyl cellulose (HPMC)|
Hydrophobic excipient with core:
Avicel pH 102
|HPMC-coated drug improved the hygroscopicity of pure drug slightly but it remained hygroscopic, as it softened in 2–3 days under ambient condition in comparison to the pure drug which transformed from solid to liquid state in 10 min.|
To improve hygroscopicity, water-insoluble excipient (Avicel pH 102) was added into the HPMC coating. The tablets did not show significant increase in moisture absorption up to 2 weeks at all conditions at 25 °C/60%RH, 30 °C/65%RH and 40 °C/75%RH,
|Sennae fructus tablets||Dry powdered lipids coating: Hot-melt coating|
Coating of enteric coating: Fluid bed
Medium chain triglyceride
(MCT), Stearic acid (SA), Precirol® ATO 5 (Pr), Compritol® 888 ATO (Cp)
Aq enteric coating: Eudragit® L 30D-55 (EuL55)
|The moisture permeability of the lipids follow this order: SA > MCT > Pr ~ Cp|
Only with Pr did the addition of EuL55 reduce moisture absorption. Other subcoatings of lipids with the addition of EuL55 showed no difference in their moisture absorption compared with just EuL55.
The maximum reduction in hygroscopicity compared with tablet cores quantifies to 98% at 33%RH/RT, 96% at 43%RH/RT (Cp10 + EuL55 10) and 85% at 75%RH/RT (Pr10 + EuL55 10).
|Fructose||One step dry-coated tablets (OSDRC) by compression||Crystallized compressed amorphous sucrose|
Hydroxypropyl cellulose (HPC) and poly(vinylpyrrolidone) (PVP)
|OSDRC tablets’ water vapor adsorption at 25 °C/75% in 15 h amount to a weight change of <1.0% in comparison to 5.5–6.0% in HPMC-coated tablets, showing its superior moisture-protective properties.|||
|Technique||Wall Material||Key Findings||Ref.|
|Casein Hydrolysate||Spray-drying||Soy Protein Isolate|
|Encapsulation increased hygroscopicity from 53 g/100 g to 106.99 g/100 g and 102.12 g/100 g, respectively, with SPI:hydrolysate ratios 70:30 and 80:20.|||
|Hygroscopicity of encapsulated hydrolysate was significantly less than free hydrolysate, improving from 53 g/100 g to 13.93 g/100 g (10DE) and 13.13 g/100 g (20DE).|||
|Casein hydrolysates||Spray-drying||Maltodextrin (MD)||The microencapsulation process by MD (60% MD) significantly reduced values of hygroscopicity.|||
|Flaxseed protein hydrolysates||Spray-drying||Maltodextrin (MD)||Hygroscopicity of encapsulated hydrolysate was significantly less than free hydrolysate, improving from from 39.2% to 17.4% in powders produced with carrier ratio 3:1.|||
|Chicken meat protein hydrolysate||Spray-drying||Maltodextrin (MD)|
Gum Arabic (GA)
|Hygroscopicity of encapsulated hydrolysate was significantly less than free hydrolysate, improving from 40.9 g/100 g to 15.9 g/100 g with 30% MD and 21.2 g/100 g with 30% GA.|||
|Amaranthus Betacyanin Pigments||Spray-drying||Maltodextrin:|
Modified corn starch
|Hygroscopic properties increased with decreasing Mw of the wall materials.|
Hygroscopicity improved from 44.6–46.0 g/100 g to 40.9 g/100 g at the lowest DE investigated (i.e., 10DE MD). Corn starch gave the lowest hygroscopicity at 24.6 g/100 g.
|Cactus pear juice||Spray-drying||Maltodextrin:|
|Hygroscopicity varied from 36.30–48.93 g/100 g.|
The least hygroscopic powders were obtained at the highest MD concentrations and pressure.
|The lowest hygroscopicity values were obtained when the highest MD concentrations used.|
Lower inlet air temperature and higher feed flow led to lower hygroscopicity.
|Jujube powder||Spray-drying||Maltodextrin (MD)||Hygroscopicity was significantly affected by weight ratio of MD and feed flow rate (FFR). Lower hygroscopicities were obtained at higher MD and FFR. The highest MD concentration resulted in the least hygroscopicity. The optimum formulation had a hygroscopicity of 18.59%.|||
1. -butyl-3-methylimidazolium Ibuprofenate (BMIm Ibu)
1. -butyl-3-methyl imidazolium Warfarinate (BMIm War)
Choline Ibuprofenate (Cho Ibu)
Choline Warfarinate (Cho War)
Propranolol Saccharin (Pro Sac)
|The physical stabilities of API-ILs encapsulated were tested by storing them at 25 °C/50%RH for up to 14 days. API-ILs encapsulated by MD were found to rapidly absorb water and transform from fine powder into extremely viscous sticky treacle-like liquid. In contrast, API-ILs encapsulated by EC remained as fine white powder and appeared unchanged upon storage.|||
|Whey protein hydrolysate||Spray-drying||Maltodextrin and β-cyclodextrin (MD and β-CD)|
|Hygroscopicity of encapsulated hydrolysate was significantly less than free hydrolysate, improving from 64.31 g/100 g to 43.09 g/100 g for MD-encapsulated and 36.99 g/100 g for MD/β-CD (1:1 w/w) encapsulated hydrolysate (70% wall).|||
|Casein hydrolysate||Spray-drying||Gelatin and Soy Protein Isolate (GE and SPI)||All formulations were less hygroscopic than free hydrolysate, with the lowest at 27.23 g/100 g (20% hydrolysate, 80% carrier, (wall materials: 40% GE, 60% SPI)) compared to 53 g/100 g for free hydrolysate. Variations in GE and SPI concentration did not cause significant differences in hygroscopicity.|||
|Purple sweet potato||Spray-drying||Maltodextrin|
(MD) and α-amylase
|Hygroscopic moisture of spray dried flours treated with MD was at 2.9–3.0 g/kg, exhibiting lower hygroscopicity than control at 3.3 g/kg.|
Hygroscopicity increased at higher levels of amylase.
|Whey protein hydrolysate||Spray-drying|
|Whey Protein Concentrate and Sodium Alginate|
(WPC and ALG)
|Hygroscopicity of encapsulated hydrolysate obtained via both methods were significantly less than free hydrolysate.|
For spray-drying, the hygroscopic moisture of free hydrolysate at 26.69 g/100 g was reduced to 20.31 g/100 g (WPC) and 20.93 g/100 g (WPC/ALG).
For freeze-drying, the hygroscopic moisture of free hydrolysate at 31.09 g/100 g was reduced to 26.28 g/100 g (WPC) and 24.40 g/100 g (WPC/ALG).
|Soy Protein Isolate and Maltodextrin (SPI and MD)||Hygroscopicity of encapsulated hydrolysate obtained via both methods were significantly less than free hydrolysate.|
For spray-drying, the hygroscopic moisture of free hydrolysate at 39 g/100 g was reduced to 18–20 g/100 g.
For freeze-drying, the hygroscopic moisture of free hydrolysate at 41 g/100 g was reduced to 27–28 g/100 g.
|Technique||Wall Material||Key Findings||Ref.|
|Soybean Protein Isolate/Chitosan|
|Microencapsulated capsanthin had enhanced stability against low and medium RH where it had improved retention rates from 42.77%, 54.37%, and 56.69% to 81.01%, 80.71% and 73.79% in RH 33%, 58%, 68%, respectively.|
It was less effective in protecting capsanthin in high humidity of 98%RH where its retention rate worsened from 68.99% to 45.81%.
|Polyphenols from grape Juice Extract (GJE)||Extrusion into solution for complex coacervation|
|Gelatin/i-Carageenan (GE/i-Car)||Water uptake capacity (WU) is directly related to hygroscopicity.|
Blends containing higher amounts of GE had slightly lower WU. The lowest WU was observed at GE/i-Car at ratio 85:15, lower than that of 100% GE.
WU between 8–12% was lower than WU of GJE at 32% after 100 h, showing how the freeze dried matrices can reduce the hygroscopicity of GJE.
|Aspartame||Double emulsion complex coacervation|
|Hygroscopicity were in the range of 10.73–13.43 g/100 g for all formulations, with no significant difference from free aspartame at 10.86 g/100 g.|||
|Anthocyanin||Double emulsion complex coacervation|
|Hygroscopicity ranged from 36–49 g/100 g, which was significantly less than anthocyanin at 85.22 g/100 g.|||
|Anthocyanin||Double emulsion complex coacervation|
|Hygroscopicity ranged from 37.05–49.05 g/100 g, which was significantly less than anthocyanin at 94.60 g/100 g.|||
|Anthocyanin and tea extracts||Double emulsion complex coacervation|
Freeze dried extracts (FDE)
Spray dried extracts (SDE)
|Moisture content of SDE microcapsules at 2.39% and 3.23% were significantly lower than that of FDE at 4.88% and 4.91%, for GE/AG and CS/CMC-encapsulated capsules, respectively. GE/AG capsules had lower moisture content than CS/CMC capsules as CS/CMC layer was thicker, but their hygroscopicity difference was not large.|
SDE capsules had lower hygroscopicity at 21.4% and 21.8% than FDE microcapsules at 45.2% and 43.5%, for GE/AG and CS/CMC-encapsulated capsules, respectively.
|Casein Hydrolysate||Double emulsion complex coacervation|
|Soybean Protein Isolate/Pectin|
|Hygroscopicity of free hydrolysate at 53 g/100 g was almost two times higher than the encapsulated samples at 20.08–24.38 g/100 g.|
The lowest value was obtained at the lowest hydrolysate content (50%). The more the content, the more hygroscopic the sample.
|Mildronate||Double emulsion complex coacervation|
Dried at ambient temperature
Poly(lactic acid) (PLA)
|The polymer coatings decreased mildronate’s hygroscopicity in the long run (75%RH at 168 h) by more than two times, from 66.28%, to 26.18% in PLA and 22.04% in PS.|||
|Probiotic Lactobacilli||Emulsification and external gelation/crosslinking|
Whey Protein Isolate (WPI)
All formulations have sucrose:
|The order of hygroscopicity is as follows ALG/WPI > ALG > ALG/WPI/LAC > ALG/LAC based on moisture absorption isotherms and vapor absorption rates of the microcapsules.|
LAC addition had significantly reduced hygroscopicity, which can be seen in the storage stability afforded by the encapsulation, in the otherwise quick inactivation of probiotics.
|Nitrofurantoin anhydrate||Wet granulation||Amorphous:|
Low-substituted Hydroxypropyl cellulose (HPC)
Partially amorphous: Silicified Microcrystalline cellulose (MCC)
|Only the amorphous excipients impeded hydrate formation of the drug at high water content.|
The hygroscopic partially amorphous excipient hindered hydrate formation of drug at low water contents.
The crystalline excipient was unable to control hydrate formation of drug.
|Ginsenoside from Red Ginseng Extract||Dissolution and freeze drying|
|Silicon Dioxide (SiO2)||The water sorption rate of the|
extract was at <20% from 30%RH to 70%RH, compared to solid dispersion with SiO2 at <12%.
Visual observation of the solid dispersion yielded no observable differences before and after storage in various humid conditions, from 30% to 70%RH for 25 days at 30 °C.
The desorption isotherms show that the dispersion had negligible hysteresis, which showed the reversible change in water content and the non-hygroscopic nature of the powder.
|Aspirin (Acetylsalicylic Acid)||Physical mixture||Highest to lowest crystallinity: Cladophora cellulose|
Microcrystalline cellulose (MCC-SLM)
Agglomerated micronized cellulose
Low crystallinity cellulose (LCC)
|The lowest degradation rates were found in formulations consisted of the lowest crystallinity LCC despite its highest moisture.|||
|Aspirin (Acetylsalicylic Acid)||Physical mixture||High crystallinity cellulose (HCC)|
Microcrystalline cellulose (MCC)
Low crystallinity cellulose (LCC)
|Drug degradation increased with high amounts of crystallinity cellulose HCC and MCC. It was lowest and decreased with higher amount of LCC despite its higher moisture content.|||
|Traditional Chinese Medicines (TCM)||Powder: Wet granulation|
Tablets formation: Compression
|Porous calcium silicate (Florite RE, FLR)||Wet granulation was a success with the addition of FLR.|
It is suitable for use in wet granulation of very hygroscopic powders as water retained in FLR will be transferred to the added hygroscopic material very slowly, resulting in granules.
|Limaprost||Dissolution and freeze drying||Dextran40|
|Although water content after storage was extremely high at >10%, the drug was stabilized.|||
T10, T40, T70
|The moisture sorption was depressed by increasing mass of dextrans.|
Dextran also increased the Tg of the extracts at all RH, reducing their tackiness and ability to absorb water.
|Physalis peruviana fruit extract||Wet granulation|
Oven drying Or
Fluidized bed drying
|Combination of corn starch and Microcrystalline cellulose (MCC)||The formulation improved the hygroscopicity of powder slightly, changing it from class III (moderately hygroscopic) to class II (slightly hygroscopic) powder. It also helped to avoid deliquescence of the extract.|||
|Raw date||Physical mixture|
|Maltodextrin (MD)||MD increased Tg The higher the MD content, the lower the hygroscopicity. Hygroscopicity value was 6.2% at MD to date ratio of 35:65, and 4.0% at 50:50.|
MD:date at 50:50 remained free flowing even after a year of storage.
|Betahistine dihydrochloride||Direct compression||Quick Tab™ (mix of tricalcium phosphate, microcrystalline cellulose, povidone, cross povidone)||After 3 months in 25 °C/60%RH accelerated stability testing conditions, the formulation appearance was found to be satisfactory with no change. Its weight variation was also insignificant.|||
|Betahistine (BTH)||Kneading and oven drying|
Dissolution and freeze drying
|Compared with BTH which liquefied completely after 100 min, the solids obtained from both kneading and freeze drying were not completely liquefied even after a month.|
At 300 h in 75%RH, BTH’s weight varied by 70–80%, compared with that of the solids obtained by both methods which increased by <10%.
At 240 min in 33%RH, BTH completely liquefied, compared with the weight variation in the solids obtained by both methods which increased by <10%.
|Phloroglucinol (SPF)||Solvent evaporation||Progesterone (Prog)||In dynamic vapor sorption, SPF absorbed 25% water to convert to dihydrate at 40%RH.|
Prog-SPF and Prog-SPF-HH (hemihydrate) had remarkable hygroscopic advantage over SPF, as they absorbed 0.5% and 0.3% water, respectively, at 80%RH. Furthermore, Prog-SPF absorbed 0.3% and 0.4% water at 60% and 80%RH in 2 weeks, showing their non-hygroscopic nature.
|Berberine Chloride (BCl)||Solvent evaporation||Succinic acid (SUA)|
Glutaric acid (GLA)
Adipic acid (ADA)
Pimelic acid (PIA)
|In dynamic vapor sorption, BCl absorbed 8.1–10% water to convert to dihydrate from 10% to 70%RH, and absorbed 11– 16% water to convert to tetrahydrate from 80% to 90%RH.|
All cocrystals adsorbed negligible amounts of moisture of <1.2% up to 70%RH. Hygroscopicity follows the ascending order of BCI-SUA < BCl-GLA < BCl-ADA < BCl-PIA < BCl.2H2O.
BCl-SUA and BCI-GLA were less hygroscopic than the other 2 cocrystals as they did not form hydrates when exposed to high RH.
|Isosorbide (ISO)||Solvent evaporation||Piperazine (PZ)|
3,5-dihydroxybenzoic acid (35DHBA)
Gallic acid (GaA)
|The critical RH of cocrystals at 56–85%RH were higher than that of of ISO at 48%RH.|
At 95%RH, ISO and ISO-PZ deliquesced, whereas ISO-HCT, ISO-35DHBA and ISO-GA remained solid.
|Palmatine Chloride (PMTCl)||Solvent evaporation||Gallic acid (GaA)||The hygroscopic stability of PMTCl-GA salt cocrystals were significantly better than PMTCl. At 75%, 80% and 95%RH, PMTCl took more days to reach moisture equilibrium to gain 7.07%, 16.46% and 19.01% water mass at each RH, respectively, as compared to 2.83%, 4.84% and 5.78% moisture gained by PMTCl-GA.|||
|Metformin (MET)||Solvent evaporation||Epalrestat (EP)||The hygroscopicity of MET and METCl (commercial) were higher than EP-MET and EP-MET monohydrate (MH). At 95%RH, the weight of MET increased 63%, EP-MET increased 0.25%, EP-MET MH increased <1%, and METCl increased 1.54%.|||
|Sodium Valproate (VAL)||Solvent evaporation|
|TMA-VAL absorbed almost no water at <1% up to 75%RH after 1 week, whereas sodium VAL absorbed 70.02%.|
CBM-VAL absorbed <10% at 100%RH after 1 week, whereas sodium VAL absorbed 144.69%.
|Amorphous vemurafenib (VEM)||Liquid-assisted grinding|
|D-camphorsulfonic acid (D-CSA)|
L-camphorsulfonic acid (L-CSA)
DL-camphorsulfonic acid (DL-CSA)
|Improved hygroscopicity was observed as amorphous VEM absorbed 2.45% water at 95%RH, and cocrystals VEM-D-CSA, VEM-L-CSA, and VEM-DL-CSA absorbed 1.05%, 1.10% and 1.17%, respectively.|||
|Berberine Chloride (BCl)||Liquid-assisted grinding||L-Lactic acid (LA)||In dynamic vapor sorption, BCl rapidly absorbed water at 8.8% to convert to dihydrate from 0% to 10%RH, remained stable up to 70%RH, and absorbed significant amount of water from 70% to 90%RH to convert to tetrahydrate.|
BCl-LA gained insignificant moisture at 0.3% from 0 to 10%RH, remained stable up to 70%RH, and absorbed 2 water molecules to become BCl-LA.H2O from 70% to 95%RH. The cocrystal exhibited lower hygroscopicity than BCl.
|Berberine Chloride (BCl)||Liquid-assisted grinding||Citric acid (CA)||In dynamic vapor sorption, BCl rapidly absorbed water to convert to dihydrate from 0% to 10%RH, gained weight gradually via surface water adsorption to 70%RH, and absorbed significant amount of water to become tetrahydrate from 70% to 90%RH.|
BCl-CA gained insignificant moisture at < 2% from 0 to 70%RH, gained moisture gradually at 8% from 70% to 95%RH.
The lack of significant hysteresis and step weight gain from 70% to 95%RH showed that BCl-CA did not transform to a hydrate at 95%RH, and that it exhibited greater physical stability over BCl.
|Levofloxacin (LVFX)||Neat grinding||Metacetamol (AMAP)||In dynamic vapor sorption, LVFX absorbed water at 2.2% to become a hydrate when RH increased from 0% to 10%.|
LVFX-AMAP absorbed water at 0.3% at 95%RH, indicating its non-hygroscopic properties.
|L-Lactic acid (LA)||Melt crystallization||D-tryptophan|
|In dynamic vapor sorption, LA deliquesced and had a net increase of 1.3157 g/g sample between 0% to 90%RH, compared to the little mass increase in cocrystals at 0.0017 g/g sample of LA-D-T and 0.0299 g/g sample for LA-3-N. Visual observation at RH96% confirmed the deliquescence of LA, and how both cocrystals remained the same.|||
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Ng, L.H.; Ling, J.K.U.; Hadinoto, K. Formulation Strategies to Improve the Stability and Handling of Oral Solid Dosage Forms of Highly Hygroscopic Pharmaceuticals and Nutraceuticals. Pharmaceutics 2022, 14, 2015. https://doi.org/10.3390/pharmaceutics14102015
Ng LH, Ling JKU, Hadinoto K. Formulation Strategies to Improve the Stability and Handling of Oral Solid Dosage Forms of Highly Hygroscopic Pharmaceuticals and Nutraceuticals. Pharmaceutics. 2022; 14(10):2015. https://doi.org/10.3390/pharmaceutics14102015Chicago/Turabian Style
Ng, Liu Han, Jordy Kim Ung Ling, and Kunn Hadinoto. 2022. "Formulation Strategies to Improve the Stability and Handling of Oral Solid Dosage Forms of Highly Hygroscopic Pharmaceuticals and Nutraceuticals" Pharmaceutics 14, no. 10: 2015. https://doi.org/10.3390/pharmaceutics14102015