Data-driven approach to mitigate quality impact of hygroscopic pharmaceutical raw materials throughout the supply chain

Figures & data

Figure 1. Focus points in the supply chain for hygroscopic raw material controls.

Table 1. Hygroscopicity classification.

European pharmacopoeia (EP)		Hygroscopicity classification
Increase in mass at 80% RH/24h  (%)	EP terminology
<0.2	NA	H-1
0.2–2.0	Slightly hygroscopic	H-2
2–15	Hygroscopic	H-3
>15	Very hygroscopic	H-4

Table 2. Data supporting hygroscopicity classification of excipients.

Raw material	Crystallinity pre-DVS	Weight loss (% wt to Temp °C)	% Weight change (25 °C)			Crystallinity	Hygroscopicity classification
			30% RH (%)	65% RH (%)	80% RH (%)	Post-DVS
β-Cyclodextrin	Crystalline	12.5% to 150	1.2	1.5	1.9	Same	H-3
Betadex Sulfobutyl Ether Sodium (Captisol®)	Amorphous	9.4% to 150	−0.2	11.1	24.8	Liquid	H-4
Calcium Acetate	Crystalline	1.9% to 175	−0.1	0.5	1.0	Different	H-2
Carboxymethylcellulose Sodium	Amorphous	8.4% to 150	1.6	11.7	22.3	Same	H-4
Carnauba Wax	Crystalline	0.1% to 150	0.0	0.1	0.1	Same	H-1
Citric Acid (Lot 1)	Crystalline	0.0% to 150	0, 0	0, 0	16.6, 2.9	Liquid, Same	H-4
Citric Acid (Lot 2)	Crystalline	0.0% to 150	0, 0	0, 0	45.9, 10.4	Liquid, Liquid	H-4
Colloidal Silicon Dioxide	Amorphous	0.2% to 150	0.0	1.0	2.9	Same	H-3
Copovidone (Kollidon VA 64)	Amorphous	3.6% to 150	0.0	8.7	17.4	Liquid	H-4
Croscarmellose Sodium (Ac-Di-Sol)	Amorphous	7.3% to 175	−0.4	7.4	14.6	Same	H-3
Crospovidone (Polyplasdone XL)	Amorphous	6.8% to 125	2.4	14.0	23.9	Same	H-4
Dicalcium Phosphate	Crystalline	0.2% to 175	0.0	0.0	0.1	Same	H-1
Fumaric Acid	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
Glyceryl Dibehenate (Compritol® 888 ATO)	Crystalline	0.6% to 150	0.0	0.4	0.8	Same	H-2
Hydroxypropyl Methylcellulose (Methocel^TM K100LVCR)	Amorphous	2.9% to 150	−0.4	5.9	11.0	Same	H-3
Hydroxypropyl Methylcellulose (Methocel^TM K100MCR)	Amorphous	2.9% to 150	0.0	5.9	11.0	Same	H-3
Hydroxypropyl Methylcellulose (Methocel^TM K15MCR)	Amorphous	2.6% to 150	0.1	7.3	12.3	Same	H-3
Hydroxypropyl Methylcellulose (Methocel^TM K3LV)	Amorphous	2.4% to 150	−0.2	5.0	10.5	Same	H-3
Hydroxypropyl Methylcellulose (Methocel^TM K4MCR)	Amorphous	4.0% to 150	−0.5	7.0	12.1	Same	H-3
Hydroxypropyl Methylcellulose Acetate Succinate	Amorphous	1.4% to 150	0.1	2.6	4.6	Same	H-3
Hydroxypropylcellulose (Klucel EXF)	Amorphous	1.2% to 100	0.0	4.8	9.4	Same	H-3
Indigo Carmine (Acid Blue 74)	Crystalline	5.6% to 150	0.2	1.3	8.0	Same	H-3
Lactose (Sheffield^TM DT)	Crystalline	0.5% to 150	0.0	0.0	0.5	Same	H-2
Magnesium Stearate (HyQual®)	Crystalline	3.6% to 125	0.0	0.1	0.2	Same	H-1
Maize Starch	Crystalline	7.9%, 11.3% to 175	0, −2.0	4.2, 3.2	8.0, 6.2	Same, Same	H-3
Maltodextrin	Amorphous	6.4% to 175	−0.2	4.7	10.4	Same	H-3
Mannitol	Crystalline	0.1% to 175	0, 0	0, 0.1	0.1, 0.2	Same, Same	H-2
Microcrystalline Cellulose (Avicel® PH-101)	Crystalline	4.0% to 125	−0.1	2.8	5.0	Same	H-3
Microcrystalline Cellulose (Avicel® PH-102)	Crystalline	3.8% to 150	−0.1	2.7	4.9	Same	H-3
Microcrystalline Cellulose (Avicel® PH-200)	Crystalline	3.6% to 150	−0.4	3.1	5.4	Same	H-3
Myo-Inositol	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
N-Lauroylsarcosine sodium (Sarkosyl NL)	Crystalline	0.8% to 125	3.0	2.1	3.4	Amorphous	H-3
Opadry® II	Crystalline	1.3% to 150	−0.3	2.0	4.2	Same	H-3
Opadry® II Blue	Crystalline	1.7% to 175	−0.4	2.0	3.9	Same	H-3
Opadry® II Clear	Crystalline	1.6% to 150	−0.2	2.7	5.7	Same	H-3
Opadry® II White	Crystalline	9.5% to 175	−0.4	1.5	2.7	Same	H-3
Opadry® II Yellow	Crystalline	1.0% to 150	0.0	2.5	4.4	Same	H-3
Pentetic Acid	Crystalline	NA	0.0	0.0	0.0	Same	H-1
Poloxamer 188 (Kolliphor® P 188)	Crystalline	0.3% to 150	−0.1	0.6	1.2	Same	H-2
Potassium Phosphate Dibasic	Crystalline	0.0% to 200	0.5, 1.6	18.8, 16.9	99.3, 108.5	Liquid, Liquid	H-4
Potassium Phosphate Monobasic	Crystalline	0.0% to 200	0, 0	0, 0	0, 0	Same, Same	H-1
Povidone (Plasdone K-29/32)	Amorphous	5.9% to 125	3.3	14.1	27.2	Liquid	H-4
Sodium Dodecyl Sulfate	Crystalline	NA	0.0	0.2	2.2	Same	H-3
Sodium Phosphate Dibasic	Crystalline	0.3% to 150	0.0	3.7	26.6	Different	H-4
Sodium Starch Glycolate (Explotab®)	Amorphous	8.0% to 150	0.0	7.4	20.0	Same	H-4
Sodium Stearyl Fumarate (PRUV®)	Crystalline	3.0% to 150	0.0	0.0	0.0	Same	H-1
Soluplus®	Amorphous	2.7% to 175	−0.5	3.8	9.6	Same	H-3
Stearic Acid	Crystalline	0.0% to 125	0.0	0.0	0.0	Same	H-1
Succinic Acid	Crystalline	0.0% to 125	0.0	0.0	0.1	Same	H-1
Sucrose	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1

Soluplus^®: Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; NA: not available; Same: XRPD before and after DVS experiment are identical; Different: XRPD before and after DVS experiment are not identical; Liquid: Material partially or fully deliquesced to liquid state.

Table 3. Data supporting hygroscopicity classification of chemicals.

Raw Material	Crystallinity pre-DVS	Weight Loss (%wt to Temp °C)	% Weight Change (25 °C)			Crystallinity post-DVS	Hygroscopicity classification
			30% RH (%)	65% RH (%)	80% RH (%)
(alpha)-Lipoic Acid	Crystalline	0.2% to 150	0.0	0.0	0.0	Same	H-1
1,4-Dithiothreitol (DTT)	Crystalline	1.5% to 125	0.0	0.4	9.9	Liquid	H-3
2-(N-Morpholino)ethanesulfonic Acid (MES)	Crystalline	NA	7.3	1.2	1.2	Different	H-3
2-(N-Morpholino)ethanesulfonic Acid Potassium (MES Potassium)	Crystalline	NA	0.0	0.2	68.8	Liquid	H-4
2-(N-Morpholino)ethanesulfonic Acid Sodium (MES sodium)	Crystalline	3.8% to 100	0.0	11.9	28.2	Different	H-4
3-(Cyclohexylamino)-1-propanesulfonic Acid (CAPS)	Crystalline	1.9% to 100	0.0	0.6	1.5	Different	H-2
3-(N-Morpholino)propanesulfonic Acid (MOPS)	Crystalline	0.0% to 150	0.0	0.0	8.6	Different	H-3
3-(N-Morpholino)propanesulfonic Acid Sodium (MOPS Sodium)	Crystalline	2.5% to 100	0.0	12.1	24.5	Liquid	H-4
Ammonium Ferric Citrate	Amorphous	11.0% to 175	3.2	7.9	17.5	Liquid	H-4
Ammonium Sulfate	Crystalline	0% to 150	0.0	0.0	0.0	Same	H-1
Aurintricarboxylic Acid	Amorphous	7.1% to 175	0.0	1.0	3.9	Same	H-3
Aurintricarboxylic Acid Ammonium	Amorphous	NA	0.1	5.2	11.7	Same	H-3
Betaine	Crystalline	1.7% to 150	1.8	14.9	101.9	Liquid	H-4
Betaine Hydrochloride	Crystalline	NA	0.0	0.0	0.2	Different	H-1
Bis-Tris	Crystalline	0.2% to 150	0.0	0.2	0.6	Same	H-2
Bis-Tris Propane	Crystalline	0.0% to 175	0.0	0.0	0.0	Same	H-1
Boric Acid	Crystalline	0.1% to 100	0.0	0.0	0.0	Same	H-1
Butyric Acid Sodium	Crystalline	0.2% to 150	0.0	2.2	148.5	Liquid	H-4
Caffeine	Crystalline	0.1%, 0.3% to 150	0, 0	0.1, 0	0.1, 0.1	Same, Same	H-1
Calcium Chloride	Crystalline	45.0% to 175	26.6	43.2	177.3	Liquid	H-4
Choline Chloride	Deliquesced	1.0% to 175	10.1	28.6	83.1	Liquid	H-4
Cystamine Dihydrochloride	Crystalline	0.0% to 150	0.0	0.0	30.7	Liquid	H-4
Cysteamine Hydrochloride	Amorphous	0.9% to 175	−0.6	24.9	84.6	Liquid	H-4
Dextrose (Supplier 1, Lot 1)	Crystalline	0% to 150	0, 0, 0	0.1, 0, 0	0.6, 0.4, 0.6	Different, NA, NA	H-2
Dextrose (Supplier 1, Lot 2)	Crystalline	NA	0, 0	0, 0	0.3, 0.3	Different, NA	H-2
Dextrose (Supplier 2)	Crystalline	0% to 150	0, 0	0, 0.1	4.2, 1.9	Different, NA	H-3
D-(+)-Galactose	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
D-Biotin	Crystalline	0.0% to 175	0.0	0.0	0.0	Same	H-1
D-Pantothenic Acid	Amorphous	6.7% to 150	−0.2	2.6	8.0	Liquid	H-3
Ferric Ammonium Citrate	Amorphous	5.0% to 150	1.2	14.3	27.7	Liquid	H-4
Folic Acid (dihydrate)	Crystalline	7.5% to 175	0.0	0.3	0.5	Same	H-2
Guanidine Hydrochloride	Crystalline	0.0% to 150	0.0	6.6	87.7	Liquid	H-4
Hexafluorophosphate Benzotriazole Tetramethyl Uronium (HBTU)	Crystalline	0.1% to 150	0.0	0.0	0.0	Different	H-1
Hexamethylene Bisacetamide (HMBA)	Crystalline	0.2% to 150	0.0	0.0	0.0	Same	H-1
Hydrocortisone	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
Imidazole	Crystalline	0.3% to 100	0.0	0.0	2.0	Different	H-3
Iron(III) Citrate (monohydrate)	Amorphous	8.1% to 150	0.0	0.7	1.7	Same	H-2
Isopropyl (beta)-D-1-thiogalactopyranoside (IPTG)	Crystalline	7.0% to 125	0.0	0.1	0.2	Same	H-2
Kanamycin Sulfate	Crystalline	0.5% to 150	0.0	0.1	0.2	Same	H-2
L-Carnosine	Crystalline	0.1% to 150	−0.1	0.0	0.1	Same	H-1
L-Cystine	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
L-Cystine Dihydrochloride	Crystalline	0.1% to 150	0.0	0.0	0.6	Different	H-2
Linoleic Acid	Amorphous	5.9% to 150	−0.3	5.6	9.5	Same	H-3
L-Methionine Sulfoximine	Crystalline	0.1% to 150	0.0	0.0	0.1	Same	H-1
Magnesium Chloride	Crystalline	1.0% to 175	49.6	48.1	192.1	Liquid	H-4
Magnesium Sulfate	Crystalline	2.2% to 175	2.1	34.6	88.3	Different	H-4
Maltitol	Crystalline	NA	0.0	0.0	0.0	Same	H-1
N-β-Ketocaproyl-DL-Homoserine Lactone	Crystalline	0.0% to 125	0.0	0.7	1.5	Same	H-2
Niacin	Crystalline	0.1% to 125	0.0	0.0	0.0	Same	H-1
Niacinamide	Crystalline	4.1% to 175	0.0	0.0	0.0	Same	H-1
Polyethylene Glycol 3000	Crystalline	0.3% to 175	−0.1	0.5	2.7	Same	H-3
Polyethylene Glycol 4000	Crystalline	0.2% to 150	0.0	0.5	1.2	Same	H-2
Polyethylene Glycol 6000	Crystalline	0.3% to 175	0.0	0.5	1.1	Same	H-2
Polyvinyl Alcohol (Mowiol® 4-88)	Amorphous	1.1% to 175	0.1	1.5	10.2	Same	H-3
Potassium Chloride	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
Potassium Hydrogen Carbonate	Crystalline	0.1% to 125	0.0	1.0	4.9	Liquid	H-3
Pyridoxine Hydrochloride	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
Riboflavin	Crystalline	0.2% to 150	0.4	1.3	5.0	Different	H-3
Sodium Acetate	Crystalline	1.9% to 75	0.8	8.8	49.9	Liquid	H-4
Sodium Bicarbonate	Crystalline	0.1% to 100	0.0	0.0	0.0	Same	H-1
Sodium Carbonate	Crystalline	0.0% to 150	0.0	0.0	22.4	Different	H-4
Sodium Chloride	Crystalline	0.0% to 150	0.0	0.0	18.5	Liquid	H-4
Sodium Deoxycholate (OmniPur®)	Crystalline	7.9% to 150	0.0	9.2	9.9	Same	H-3
Sodium Hexametaphosphate	Amorphous	0.2% to 150	0.0	5.0	48.1	Liquid	H-4
Sodium Hydroxide (pellets)	Crystalline	1.9% to 150	23.2	54.4	138.4	Liquid	H-4
Sodium Pyruvate	Crystalline	0.1% to 150	0.0	0.1	0.5	Same	H-2
Sodium Sulfate	Crystalline	0.0% to 150	0.0	0.0	0.0	Different	H-1
Sodium Thioglycolate	Crystalline	0.0% to 150	0.0	0.0	129.6	Liquid	H-4
Spermine Tetrahydrochloride	Crystalline	0.0% to 150	0.0	0.0	0.0	Same	H-1
Thiamine Hydrochloride	Crystalline	3.7% to 125	0.0	0.90	1.0	Same	H-2
Triiodothyronine Sodium	Crystalline	0.8% to 150	0.3	3.1	16.5	Same	H-4
Tris(2-carboxyethyl)phosphine Hydrochloride (TCEP-HCl)	Crystalline	0.0% to 125	0.0	0.0	9.7	Different	H-3
Tris(hydroxymethyl)aminomethane (TRIS)	Crystalline	0.0% to 150	0.0	0.0	0.0	Different	H-1
Tris(hydroxymethyl)aminomethane Hydrochloride (TRIS HCl)	Crystalline	0.0% to 120	0.0	0.0	0.1	Same	H-1
Urea	Crystalline	0.0% to 125	0.0	0.0	15.6	Liquid	H-4
Vitamin B12	Crystalline	NA	2.0	6.7	10.4	Amorphous	H-3
Zinc Chloride	Crystalline	1.0% to 175	24.2	34.2	92.7	Liquid	H-4

NA: not available; Same: XRPD before and after DVS experiment are identical; Different: XRPD before and after DVS experiment are not identical; Liquid: material partially or fully deliquesced to liquid state.

Table 4. Data supporting hygroscopicity classification of hydrates.

Raw Material	Crystallinity Pre-DVS	Weight loss (%wt to Temp °C)	Theoretical Water Content (%)	% Weight change (25 °C)			Crystallinity post-DVS	Hygroscopicity classification
				30% RH (%)	65% RH (%)	80% RH (%)
Betaine Monohydrate	Crystalline	NA	13.3	0.0	11.6	84.4	Liquid	H-4
Calcium Chloride Dihydrate	Crystalline	24.2% to 165	24.5	15.2	47.6	158.3	Liquid	H-4
Citric Acid Monohydrate	Crystalline	6.4% to 175	8.6	−0.3, −0.4	0, 0.3	4.6, 7.4	Different, Different	H-3
Cobalt Chloride Hexahydrate	Crystalline	42.1% to 175	45.0	0.0	0.6	93.7	Liquid	H-4
Cupric Sulfate Pentahydrate	Crystalline	26.3% to 155	36.0	−0.8	3.2	3.2	Different	H-1^a
Dextrose Monohydrate	Crystalline	9.3% to 175	9.1	0.0	0.1	0.3	Same	H-2
Dicalcium Phosphate Dihydrate	Crystalline	4.8% to 165	20.9	0.0	0.0	0.1	Same	H-1
Ethylenediaminetetraacetic Acid Disodium Dihydrate (EDTA)	Crystalline	9.6%, 9.7% to 235	9.7	0, 0	0, 0	0.1, 0	Same, Same	H-1
Ferric Chloride Hexahydrate	Amorphous	54.9% to 205	40.0	−0.2	28.8	135.7	Liquid	H-4
Lactose Monohydrate (Fast Flo® 316)	Crystalline	4.9% to 175	5.0	0.0	0.1	0.2	Same	H-1
Lactose Monohydrate (GanuLac® 140)	Crystalline	5.0% to 175	5.0	0.0	0.0	0.0	Same	H-1
Lactose Monohydrate (Impalpable 313)	Crystalline	5.1% to 175	5.0	0.0	0.0	0.1	Same	H-1
Lactose Monohydrate (Tablettose® 80)	Crystalline	5.7% to 175	5.0	0.0	0.0	0.0	Same	H-1
L-Asparagine Monohydrate	Crystalline	11.3% to 125	12.0	0.0	0.0	0.0	Different	H-1
L-Cysteine Hydrochloride Monohydrate	Crystalline	9.3% to 155	10.0	0.0	0.2	0.4	Same	H-2
L-Histidine Hydrochloride Monohydrate	Crystalline	3.7%, 12.0% to 175	8.6	0, 0	0, 0	0, 0	Different, Different	H-1
L-Tyrosine Disodium Dihydrate	Crystalline	14.2% to 175	13.8	0.0	12	98	Liquid	H-4
Magnesium Chloride Hexahydrate	Crystalline	46.0% to 225	53.0	−0.1	46.4	131.6	Liquid	H-4
Magnesium Sulfate Heptahydrate	Crystalline	41.9% to 175	51.0	−2.0	1.8	2.3	Different	H-1^a
Manganese Sulfate Monohydrate	Crystalline	0.0% to 175	10.6	0.0	0.1	0.3	Same	H-2
2-(N-Morpholino)ethanesulfonic Acid Monohydrate	Crystalline	8.4% to 155	8.4	0.0	0.0	0.0	Same	H-1
N-α-Acetyl-L-Arginine Dihydrate	Crystalline	13.7% to 155	14.3	0.0	0.0	0.0	Different	H-1
N-Acetyl-D-Mannosamine Monohydrate	Crystalline	5.4% to 155	7.5	0.0	0.0	0.0	Same	H-1
Sodium Acetate Trihydrate	Crystalline	38.2% to 155	39.7	0.0	0.0	19.6	Liquid	H-4
Sodium Borate Decahydrate	Crystalline	38.1% to 175	47.2	−0.1	0.0	0.5	Same	H-2
Sodium Carbonate Monohydrate	Crystalline	14.7% to 125	14.5	0.0	0.0	12.3	Same	H-3
Sodium Citrate Dihydrate	Crystalline	11.1% to 175	12.2	0.0	0.0	0.0	Different	H-1
Sodium Hydrogen Sulfate Monohydrate	Crystalline	7.0% to 175	13.0	0.0	10.3	94.5	Liquid	H-4
Sodium Molybdate Dihydrate	Crystalline	14.7% to 155	14.9	0.0	0.0	0.2	Same	H-1
Sodium Phosphate Dibasic Dihydrate	Crystalline	11.4 % to 125	20.2	0.0	0.0	5.8	Different	H-3
Sodium Phosphate Dibasic Heptahydrate	Crystalline	26.3% to 125	44.0	−11.2	2.0	11.1	Different	H-1^a
Sodium Phosphate Dibasic Dodecahydrate	Crystalline	51.7% to 155	60.3	−19.4	−2.0	−2.2	Different	H-1^a
Sodium Phosphate Monobasic Monohydrate	Crystalline	13.8% to 175	13.1	0.0	0.0	2.9	Different	H-3
Sodium Phosphate Monobasic Dihydrate	Crystalline	17.0% to 155	23.0	−1.2	2.3	9.2	Different	H-3
Sodium Phosphate Tribasic Dodecahydrate	Crystalline	51.9% to 175	56.8	−2.8	1.6	3.6	Different	H-1^a
Trehalose Dihydrate	Crystalline	9.2% to 175	9.5	0.0	0.0	0.0	Different	H-1

^aWeight loss at 30%RH due to dehydration of the hydrate was considered when assigning hygroscopicity rating; NA: not available; Same: XRPD before and after DVS experiment are identical; Different: XRPD before and after DVS experiment are not identical; Liquid: Material partially or fully deliquesced to liquid state

Table 5. Data supporting hygroscopicity classification of amino acids.

Raw material	Crystallinity pre-DVS	Weight Loss (%wt to Temp °C)	% Weight change (25 °C)			Crystallinity post-DVS	Hygroscopicity classification
			30% RH (%)	65% RH (%)	80%RH (%)
Glycine	Crystalline	0.0% to 155	0.0	0.0	0.0	Same	H-1
L-Alanine	Crystalline	0.0% to 175	0.0	0.0	0.0	Same	H-1
L-Arginine	Crystalline	NA	0, 0, 0	15.7, 15.8, 12.6	20.5, 20.5, 20.3	NA	H-4
L-Arginine Hydrochloride	Crystalline	0%, 0%, 0% to 175	0, 0, 0	0, 0, 0	0, 0.2, 0	Same, Same, Same	H-1
L-Aspartic Acid	Crystalline	0.0% to 175	0.0	0.0	0.0	Same	H-1
L-Cysteine	Crystalline	0.0% to 155	0.0	0.0	0.0	Different	H-1
L-Cysteine Dihydrochloride	Crystalline	1.8% to 155	0.0	6.1	11.8	Different	H-3
L-Glutamic Acid	Crystalline	0.0% to 155	0.0	0.0	0.0	Same	H-1
L-Glutamine	Crystalline	0.0% to 155	0.0	0.0	0.0	Same	H-1
L-Histidine	Crystalline	0.0% to 225	0.0	0.0	0.0	Same	H-1
L-Isoleucine	Crystalline	0.0% to 155	0.0	0.0	0.0	Same	H-1
L-Leucine	Crystalline	0.0% to 155	0.0	0.0	0.0	Different	H-1
L-Lysine Hydrochloride	Crystalline	0.2% to 155	0.0	0.1	19.2	Different	H-4
L-Methionine	Crystalline	0% to 155	0.0	0.0	0.0	Same	H-1
L-Phenylalanine	Crystalline	0%, 0% to 155	0, 0	0, 0	0, 0	Same, Same	H-1
L-Proline	Crystalline	0.3% to 155	−0.3	13.5	85.4	Liquid	H-4
L-Serine	Crystalline	0%, 0% to 175	0, 0	0, 0	0, 0	Different, Different	H-1
L-Threonine	Crystalline	0.2% to 175	0.0	0.0	0.0	Same	H-1
L-Tryptophan	Crystalline	0%, 0% to 175	0, 0	0, 0	0, 0.1	Same	H-1
L-Tyrosine	Crystalline	NA	0.0	0.0	0.0	Same	H-1
L-Tyrosine Hydrochloride	Crystalline	NA	0.0	0.0	−0.2	Same	H-1
L-Valine	Crystalline	0.0% to 155	0.0	0.0	0.1	Same	H-1

Same: XRPD before and after DVS experiment are identical; Different: XRPD before and after DVS experiment are not identical; Liquid: Material partially or fully deliquesced to liquid state.

Table 6. Data supporting hygroscopicity classification of media.

Raw Material	Crystallinity Pre-DVS	Composition (%wt H-3 and H-4)	% Weight Change (25 °C)			Crystallinity Post-DVS	Hygroscopicity Classification
			30% RH (%)	65% RH (%)	80% RH (%)
Media 1	Crystalline	NA	0.0	0.4	28.8	Liquid	H-4
Media 2	Crystalline	NA	0.0	0.0	0.1	Same	H-1
Media 3	Crystalline	NA	−0.2	12.4	39.4	Liquid	H-4
Media 4	Crystalline	NA	0.7	10.5	99.2	Liquid	H-4
Media 5	Crystalline	NA	0.0	0.0	0.1	Same	H-1
Media 6	Crystalline	17.5%	0.2	16.4	52.2	Liquid	H-4
Media 7	Crystalline	42.7%	1.5	18.6	53.8	Liquid	H-4
Media 8	Crystalline	31.3%	1.1	18.6	56.1	Liquid	H-4
Media 9	Crystalline	11.6%	0.2	15.1	44.3	Liquid	H-4
Media 10	Crystalline	20.2%	−0.1	11.3	33.2	Liquid	H-4
Media 11	Crystalline	NA	0.0	11.3	87.0	Liquid	H-4
Media 12	Crystalline	6.3%	−0.2	5.6	30.5	Liquid	H-4
HEPES	Crystalline	NA	0.0	0.0	18.8	Different	H-4
DMEM/F12-2X	Crystalline	NA	0, 0.1	9.2, 8.0	97.8, 82.2	Liquid, Liquid	H-4
Dulbecco's Phosphate Buffered Saline Powder	Crystalline	NA	0.0	1.9	51.2	Liquid	H-4
MEM Vitamin Powder	Crystalline	NA	−0.3	1.5	33.3	Liquid	H-4
Peptone from Casein, Pancreatic Digest	Crystalline	NA	1.1	18.4	39.4	Liquid	H-4
Soy Hydrolysate (Hy-Soy)	Amorphous	NA	1.1, 0.6, 1.2	14.0, 12.8, 19.5	43.1, 34.5, 46.7	Liquid, Liquid, Liquid	H-4
Tissue Culture Yeastolate Ultra-Filtered (Difco^TM)	Crystalline	NA	0.4	16.2	41.4	Liquid	H-4
Tryptic Soy Broth (NutriSelect^TM Plus)	Crystalline	NA	1.5	16.6	51.0	Liquid	H-4
Yeast Extract	Amorphous	NA	3.6	15.4	38.4	Liquid	H-4

HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; DMEM/F12-2X: Dulbecco’s Modified Eagle Medium/Ham’s Nutrient Mixture F12 Powder Enriched 2-fold with Supplemental Amino Acids; MEM: Minimal Essential Medium; Yeast Extract: Extract of autolyzed yeast cells (mixture of amino acids, peptides, vitamins and carbohydrates) ; Same: XRPD before and after DVS experiment are identical; Different: XRPD before and after DVS experiment are not identical; Liquid: Material partially or fully deliquesced to liquid state.

Table 7. Data supporting hygroscopicity classification of liquids.

Raw Material	% Weight Change (25 °C)			Hygroscopicity Classification
	30% RH (%)	65% RH (%)	80% RH (%)
Dimethyl Sulfoxide	NA	NA	97.9	H-4
Dimethylformamide	NA	NA	12.2^a	H-3
DL-Lactic Acid	−5.5	8.2	37.7	H-4
Ethanolamine	11.1	22.9	63.2	H-4
Glycerol	5.2	14.0	57.7	H-4
Methanesulfonic Acid	NA	NA	49.4^a	H-4
Octylphenol Ethoxylate (Triton^TM X-100)	0.9	2.9	9.0	H-3
Polypropylene Glycol	0.0	0.8	1.4	H-2
Polysorbate 20	−0.5	6.1	17.6	H-4
Polysorbate 80	−0.9	4.8	14.5	H-3
Propylene Glycol	5.6	19.1	52.3	H-4
Silicone Oil (viscosity 100 cSt at 25C)	0.0	0.0	0.0	H-1

^aValue at point of maximum weight gain before weight loss occurred; NA: not available as the experiment started at 80%RH to avoid evaporation at lower humidity

Table 8. Data supporting hygroscopicity classification of resins.

Raw Material	% Weight Change (25 °C)			Hygroscopicity Classification
	30% RH (%)	65% RH (%)	80% RH (%)
C4 Reversed Phase Resin (VYDAC® 215TP C4)	−0.2	0.8	1.1	H-2
CHT Ceramic Hydroxyapatite Resin, Type I, 40um	0.0	0.7	1.3	H-2
CHT Ceramic Hydroxyapatite Resin, Type II, 80um	0.0	0.3	0.6	H-2
Poly(ethylene oxide) Water Soluble Resin (POLYOX^TM WSR 303)	0.0	0.7	2.0	H-3

Figure 2. XRPD of L-cysteine dihydrochloride and L-cysteine hydrochloride monohydrate pre and post-DVS.

Figure 3. XRPD of L-lysine hydrochloride pre-DVS and post-DVS.

Table 9. Comparison of vapor sorption data for excipients with Murikipudi et al.

Raw Material	% Weight Change (25 °C/80% RH)
	This Work	Murikipudi et al.
Carboxymethylcellulose Sodium	22.3	23.7
Crospovidone	23.9	19.2
Dicalcium Phosphate	0.1	0.5
Dicalcium Phosphate Dihydrate	0.1	0.0
Hydroxypropyl Methylcellulose	11.0	10.4
Hydroxypropylcellulose	9.4	8.9
Lactose	0.5	0.1
Lactose Monohydrate	0.2	0.0
Magnesium Stearate	0.2	0.2
Maize Starch	8.0, 6.2	8.0
Mannitol	0.1, 0.2	0.1
Microcrystalline Cellulose	4.9	6.1
Poloxamer 188	1.2	11.0
Povidone	27.2	24.5
Sodium Starch Glycolate	20.0	22.7
Sodium Stearyl Fumarate	0.0	0.0

Figure 4. TRIS Hydrochloride (from supplier 1) temperature and relative humidity hygroscopicity limits.

Figure 5. XRPD of dextrose from supplier 1 (0.6% wt) and supplier 2 (4.2%wt) before (pre-DVS) and after the DVS experiment (post-DVS) in comparison with dextrose monohydrate.

Figure 6. Polarized light microscopy of dextrose from (A) supplier 1 and (B) supplier 2 (scale bar = 100 µm).

Table 10. Particle size distribution of dextrose from supplier 1 and supplier 2.

Sample	D10 (µm)	D50 (µm)	D90 (µm)	D4,3 (µm)
Supplier 1	68.30 +/− 17.93	228.94 +/− 14.14	351.34 +/− 5.19	221.20
Supplier 2	79.96 +/− 6.98	196.95 +/− 17.36	315.41 +/−25.44	197.04