Table 1: Bioanalytical determination of CHL

Sr. No	Drug	Sample matrix	Method	Column	Detection	Internal standard	Ref
1	CHL	Human plasma	RP-MLC	C8 reversed-phase	235 nm	Xipamide	7
2	ATN, CHL	Spiked human plasma	HPLC	Shim-pack cyanopropyl column	225 nm	HCT	8
3	CE, CHL	Biological fluids	HPLC	Hypurity C8 column	225 nm	LIS	9
4	ATN, CHL	Human breast milk	HPLC	Luna 5 µm CN column	225 nm	Guaifenesin	10
5	ATN, CHL	Human plasma	HPLC	ODS column	225 nm	Salbutamol and Xipamide	11
6	AZL, CHL	Human plasma	UFLC-MS/MS	Shimapack C-8 column	---	Valsartan	12
7	CHL	Human urine	RP-LC	HP-LiChrospher 100 RP 18	230 nm	Triamterene	13
8	CHL	Urine	HPLC	Hypenil ODs-C18(Pre-column) LiChroCART ChiraDex (Analytical column)	230 nm	---	14
9	CHL	Blood	HPLC	RP column	214 nm	Sulfanilanide	15
10	CHL	Human Plasma, Urine	HPLC	LiChrosorb RP-18	226 nm	Probenecid	16
11	ATN, CHL	Human plasma	LC–MS–MS	RP C18 column	---	Metoprolol, HCT	17
12	AZL, CHL	Human plasma	LC-MS/MS	C18 RP column	---	HCT	18
13	CHL	Urine	HPLC	RP analytical column	214 nm	---	19
14	ATN, CHL	Human plasma	UPLC-MS	UPLC BEH C18	---	Atenolol-d7 and Chlorthalidone-d4	20
15	CAN, CHL	Human plasma	UPLC–MS/MS	UPLC BEH C18	---	---	21

Table 2: Spectrophotometric methods used for determination of CHL alone and in combined dosage form

Sr. No	Drug	Matrix	Solvent	Lambda Max (nm)	Linearity (μg/mL)	Correlation coefficient (R²)	Ref.
1	CHL	Bulk and tablet	Ethanol	Zero order CHL: 275 nm, First order CHL: 275 nm	CHL:40-160	CHL: 0.998831	22
2	CHL	Bulk drug	0.2 M NaOH	CHL: 274.5	---	---	23
3	CIL, CHL	Tablet	Methanol	CIL: 271.83 nm and 278.34 nm CHL: 233.83 nm and 250.0 nm	CIL: 2-10 CHL: 2.5-12.5	CIL: 0.999 CHL: 0.9986	24
4	CHL, LOS	Bulk and tablet	Methanol	CHL: 280-290.5 nm LOS: 235-245 nm	CHL: 2-10 LOS: 4-20	CHL: 0.997 LOS: 0.999	25
5	CIL, CHL	Tablet	Methanol	CIL: 240 nm CHL: 268 nm	CIL: 2-10 CHL: 2-10	CIL: 0.998 CHL: 0.995	26
6	OLM, CHL	Tablet	Methanol	OLM: 254 nm CHL: 220 nm	OLM: 5-25 CHL: 5-25	OLM: 0.999 CHL: 0.999	27
7	OLM, CHL	Bulk and tablet	Methanol	OLM: 256 nm CHL: 275 nm	OLM: 5-20 CHL: 5-20	OLM:0.997 CHL: 0.998	28
8	CHL, NVH	Marketed Formulation	Methanol	CHL: 226 nm NVH: 282 nm	CHL: 5-25 NVH: 5-25	---	29
9	ATN, CHL	Tablet	Methanol	ATN: 318 nm CHL: 290 nm	ATN: 10‑160 CHL: 5‑25	ATN: 0.995 CHL: 0.996	30
10	MET, CHL	Tablet	Methanol	MET: 275 nm CHL: 284 nm	MET: 25-200 CHL: 25-200	MET: 0.9979 CHL: 0.9996	31
11	OLM, CHL	Tablet	Methanol	OLM; 260 nm CHL; 215 nm	OLM: 4 -32 CHL: 2.5 -20	OLM: 0.9994 CHL: 0.9993	32
12	TEL,CHL	Bulk and tablet	Methanol	TEL: 296 nm CHL: 275 nm	TEL: 4-28 CHL: 2.5- 17.5	TEL: 0.999 CHL: 0.9994	33
13	MET, CHL	Tablet	---	MET: 227.4 nm CHL: 229.8 nm	MET: 5-30 CHL: 1.3-7.9	---	34
14	AZL, CHL	Bulk and pharmaceutical	Methanol	AZL: 286 nm CHL: 257 nm	AZL: 8-50 CHL: 2-20	AZL: 0.9998 CHL: 0.9999	35
15	MET, CHL	Bulk	Methanol	MET: 267 nm CHL: 243 nm	MET: 12-28 CHL: 3-7	MET: 0.9996 CHL: 0.9991	36
16	ATN, CHL	Bulk and tablet	Methanol	ATN: 225 nm CHL: 284 nm	ATN: 10-60 CHL: 30-140	ATN: 0.999 CHL: 0.998	37

Table 3: HPLC methods used for determination of CHL alone and in combined dosage form

Sr. No	Drug name	Column	Mobile phase	Lambda max (nm)	Linearity (μg/mL)	Retention time (min)	Flow rate (mL/min)	Detector	Ref.
1.	CHL	RP C-18 column	50mM Disodium hydrogen phosphate: Methanol: Acetonitrile (70:30:05) (pH 3.5 with OPA)	220 nm	0.1 to 3.2	10.82	1	UV	39
2.	CHL	Stainless steel tube	2-Propanol:Acetic acid: Water: n -Hexane (301.5:0.5:68 v/v)	254 nm	---	---	2	UV	40
3.	CHL	HiQ Sil C8	20 mM Potassium dihydrogen orthophosphate buffer (pH 4.0): Methanol (30:70 %v/v)	230 nm	5-30	3.334±0.042	1	---	41
4.	CHL	Phenomenex Hyper Clone C 18 column	Methanol : Acetonitrile : Phosphate buffer (20mM) (pH 3.0 with OPA) (30 : 10 : 60% v/v)	241 nm	2–12	---	1	UV	42
5.	CHL	Develosil ODS HG-5 RP C18	0.1% Orthophosphoric acid : Acetonitrile : Methanol (12 : 18 : 70 v/v/v)	245 nm	0-70	7	1	UV	43
6.	CHL	Phenomenex Luna C18, 100A	Potassium dihydrogen phosphate buffer: Methanol (55:45) (pH-3.4)	244 nm	6-14	7	1	PDA	44
7.	CHL	Waters Associates Cl8 μ -Bondapak	Acetonitrile:2% Acetic acid (30: 70)	280 nm	---	---	1.5	UV	45
8.	OLM, CHL	zorbax phenyl column	Buffer (pH 3.0,mobile phase A), Acetonitrile (mobile phase B).	220 nm	10.0 to 60.0 μg/mL and 6.25 μg/mL	10.70 ±0.1 mins and 4.8 ± 0.1 mins	1.5	UV	46
9.	AMI, ATN, CHL	RP stainless steel C18 analytical column	Methanol and 0.05 M aqueous phosphate buffer adjusted to pH 4	AMI 275 nm and 225 nm for ATE and CHL	2–50, 25–150, and 2–100 μg/mL	4.07, 7.22, 13.21	1	PDA	47
10.	IBS, LOS, HTZ, CHL	Hypersil BDS	0.05 M Sodium dihydrogen phosphate buffer and acetonitrile	220 nm	10–150 μg/mL	---	1	PDA	48
11.	HTZ, CHL	LC-8-DB	1.0 mM Ammonium acetate and 2.0 mM octane sulfonic acid sodium salt in acetonitrile: water (25:75) solution. The pH was adjusted to 3.5 with GAA	254 nm	---	---	1.5	---	49
12.	AZL, CHL	ODS	0.1% Ortho phosphoric acid buffer: Acetonitrile (30:70)	230 nm	100 ppm-600ppm and 31.25ppm-187.5ppm	4.5 ±0.3 min 2.2 ±0.3 min	1	PDA	50
13.	IBS, CHL,CIL	C18 column	Buffer: Acetonitrile: TEA (80:20:0.1 %v/v/v)	222 nm	30-90 μg/mL, 1.25-3.75 μg/mL and 1-3 μg/mL	3.807 min, 4.667 min, and 6.887 min	1	UV	51
14.	CIL, ATN, CHL	Hypersil- keystone C18	Methanol :Triple distilled water (80/20 v/v) having pH 7	225 nm	10-50 μg/mL for , 10-50 μg/mL and 6- 36 μg/mL	3.25 ± 0.06, 5.36 ±0.08 and 9.02 ±0.08 min	1	UV	52
15.	CHL, AZL	Zorbax XBD-C8	Buffer (pH5.5) : Methanol (60:40)	234 nm	50.56 - 151.68 ppm and 80.010 - 240.030 ppm	6.030 and 10.997 min	1	UV	53
16.	OLM, CHL	Gemini C18	Water: Acetonitrile (55:45) with pH adjusted to 3 with OPA	250 nm	10-60 μg/mL and 5-30 μg/mL	2.95 and 3.91 min	1	UV	54
17.	AZL, CHL	BDS C18 column	Phosphate buffer: Acetonitrile (90:10). Phosphate buffer pH has been adjusted with orthophosphoric acid	260nm	10.0 to 60.0 μg/mL and 6.25 to 37.5 μg/mL	2.36±0.1 mins and 5.54±0.5 mins	0.9	PDA	55
18.	TEL, CIL, CHL	BDS hypersil C18	Methanol: Buffer (0.05M ammonium acetate) pH 5 with orthophosphoric acid (40 : 60)	270nm	20–60 μg/mL, 5–15 μg/mL and 6.25–18.75 μg/mL	3.390 min, 11.477 min, and 4.167 min	1	UV	56
19.	MET, TEL, CHL	Phenomenex C18 column	Phosphate buffer (pH adjusted to 3): Acetonitrile	310 nm	---	4.5, 7.2 and 11.01 min	1	UV	57
20.	OLM, CHL	BDS C18	10 mM Orthophosphoric acid buffer: Acetonitrile (45:55v/v)	212 nm	20 - 120 μg/mL and 6.24- 31.25 μg/mL	3.216 and 2.113 min	1	PDA	58
21.	OLM, CHL	Inertsil ODS C18	KH₂PO₄ Phosphate buffer: Acetonitrile (60: 40 v/v)	275 nm	---	13.9 ± 0.1 min. and 4.4 ± 0.5 min	1	UV	59
22.	OLM, CHL	HypersilC18	Phosphate buffer (KH₂PO₄) adjusted to pH 5.0 with dilute orthophosphoric acid and methanol in the ratio of 40: 60 % v/v	240 nm	60 - 180 μg/mL and 18.75-56.25 μg/mL	2.240min and 3.042min	1.2	PDA	60
23.	BEN, CHL	Agilent C18 column	60% NaH₂PO₄ buffer (0.1 M, pH 4.0): Methanol (40%)	262 nm	4-12 μg/mL and 12.5-37.50 μg/mL	---	1	---	61
24.	CHL, CIL	C18 column	Phase A, (0.1% Formic acid in methanol: Acetonitrile (80: 20 v/v) Phase B, (10 mM Ammonium acetate)	240 nm	---	6.047±0.2 min and 12.642 ±0.2 min	1	---	62
25.	CHL, IBS	Reverse phase column C18	0.02 M Ammonium phosphate buffer (pH 5.5): Acetonitrile: Methanol (40:40:20 v/v/v)	220 nm	40-60% μg/mL, 480 - 720 % μg/mL	---	1	UV	63
26.	AZL, CHL	Double end-capped C₁₈ column	10 mM Tris(hydroxymethyl)amino methane buffer (pH 7.7): Acetonitrile (60:40 v/v)	---	---	2.6, 4.9 min	1	---	64
27.	TEL, CHL	Agilent Extend C18	Disodium hydrogen phosphate buffer (pH:6.5): Acetonitrile	235 nm	6-18 mcg/mL and 20-60 mcg/mL	3.82 min and 14.23 min	1	PDA	65
28.	EPM, CHL	Phenomenox, Gemini C18	Water: Acetonitrile (55:45) with pH adjusted to 3.4 with ortho phosphoric acid	250 nm	10-400 μg/mL and 0.5-12.5 μg/mL	2.14 and 3.80 min	1	UV	66
29.	CHL, CIL	Inertsil ODS 3V	0.025 M Potassium dihydrogen orthophosphate buffer, pH 2.5 adjusted using dilute orthophosphoric acid (solvent A) and Acetonitrile (solvent B)	240 nm	200-600 μg/mL and 160-480 μg/mL	3.872 min and 7.668 min	1	PDA	67
30.	AZL, CHL	Eclipse XDB-C18	Methanol and potassium hydrogen phosphate buffer (pH 8, 0.05 M) (40:60,v/v)	210 nm	5.0–50.0 μg/mL and 2.5– 25.0 μg/mL	---	0.8	UV	68
31.	ATN, AMI, CHL	RP 18 column	Acetonitrile: 5mM Heptansulphonic acid sodium salt (20:80v/v, pH 4.4)	274 nm	40–160 μg/mL, 2-8 μg/mL and 10-40 μg/mL	4.2 ± 0.03, 5.1 ± 0.04, 6.5 ± 0.02 min	1	UV	69
32.	AZL, CHL	Inertsil C8 column	0.025 M Phosphate buffer pH 2.7: Acetonitrile (52.5: 47.5%)	225 nm	2.5 – 40 and 1.5 – 25 μg/mL	0.11 and 0.29 min	1.5	PDA	70
33.	CHL, LOS	C18	Acetonitrile: Water (50: 50, v/v)	220 nm	10-30 μg/mL and 20-60 μg/mL	---	1	UV	71
34.	AMB, VAL, TEL, HTZ, CHL	Cosmosil PAQ	0.05 M Sodium dihydrogen phosphate buffer: Acetonitrile	220 nm	2 –150 μg/mL	---	1	UV	72
35.	ENM, CHL	Hypersil BDS C18	Phosphate buffer: Acetonitrile: Methanol (65:25:10 v/v/v)	210 nm	5-15 μg/mL and 12.5-37.5 μg/mL	7.749 and 4.247 min	1	UV	73
36.	TEL, CHL	CAPCELL C18	Potassium dihydrogen ortho-phosphate buffer: Acetonitrile: Methanol (35: 45: 20) (pH 3.5 adjusted with OPA)	---	20–100μg/mL and 6.25–31.25 μg/mL	3.640min. and 4.937min	0.8	---	74
37.	CHL, MPS	C18	Buffer pH 4.5: Methanol : Acetonitrile (50:25:25)	223 nm	5-15 μg/mL and 20-60 μg/mL	4.390 and 6.127 min	1	UV	75
38.	BEN, CHL	C18 Kromasil column	Methanol: 0.1M Dipotassium hydrogen phosphate buffer (40:60 v/v)	260 nm	2 - 6 μg/mL and 6.25 - 18.75 μg/mL	---	1	PDA	76
39.	AZL, CHL	C 18G column	Acetonitrile: 0.1% Trifluoroacetic acid in water (40:60%v/v)	240 nm	5-80 μg/mL and 2.5-25 μg/mL	6.982 and 7.748 min	0.8	UV	77
40.	AZL, CHL	C18 column	Methanol: Water: Acetonitrile : 0.1% Ortho phosphoric acid (30:35:15:5 v/v/v/v)	251 nm	---	3.923min and 7.208 min	0.9	UV	78
41.	CIL, CHL	---	Methanol: Water (80: 20 v/v)	231.6 nm	10–70 μg/mL and 10–70 μg/mL	---	1	UV	79
42.	AZL, CHL	UPLC BEH C18	0.02% Trifluoroacetic acid in water: Acetonitrile	225 nm	40 and 12.5 μg/mL	---	0.3	---	80
43.	BEN, TEL, CHL	C18	Buffer (pH 3.0): Methanol (50:50 v/v)	230 nm	2-6 μg/mL, 20-60 μg/mL and 6.25-18.75 μg/mL	6.690 min, 8.813 min and 4.887 min	1	PDA	81
44.	CHL, ATN	C18	0.1M KH₂PO₄: Methanol (65:35)	256nm	50 μg/mL to150 μg/mL and 50 μg/mL to150 μg/mL	3.346 and 3.931 min	1	PDA	82
45.	MPS, CHL	Inertsil ODS column	10mM Ammonium Acetate: Acetonitrile (70:30% v/v)	220nm	5-25 μg/mL and 2-6 μg/mL	5.6 and 7.5 min	1	PDA	83
46.	ATN and CHL	C18	Methanol:0.01 M Potassium dihydrogen phosphate (30:70 v/v pH 3.5)	214nm	10-1000 μg/mL and 0.05-20 μg/mL	---	---	UV	84
47.	CHL and CLH	Zorbax ODS Column	1. 50% Methanol + 50% Water filtered through 1μm porosity membrane 2. 65% Methanol + 35% pH 7.9 Buffer solution (0.0022 M KH₂P0₄ and 0.016 M Na₂HPO₄)	254 nm	---	---	---	---	85
48.	MPS and CHL	Inertsil ODS 3 column	Diammonium hydrogen phosphate buffer (pH 5.5): Methanol (70:30 v/v)	254 nm	50-300 μg/mL and 12.5-75 μg/mL	6.91 min and 9.94 min	1	---	86

Table 4: HPTLC methods for determination of CHL

Sr.

Name of drug

Formulation

Stationary phase plates

Mobile phase composition

Detection

(nm)

Linearity

Ref

CHL,

CIL

Bulk and tablet

Precoated silica gel F254

RP-18 Silica gel F254 S

Toluene: Ethyl acetate: Methanol (3.2:1.3:0.5 v/v/v)

Methanol: Water (3.2:1.8 v/v

275 nm

CHL:250-1500 ng/b,

CIL:200-1200 ng/b

CHL:250-1500 ng/b

CIL: 200-1200 ng/b

CHL:0.34 ± 0.02,

CIL: 0.79 ± 0.02

CHL:0.24 ± 0.02,

CIL: 0.81 ± 0.02

TEL,

CHL

Bulk and Tablet

Pre coated with silica gel 60F254

---

Toluene: 2-Propanol: 25% Ammonia (6.5:3.5:0.2 v/v/v)

---

257 nm

TEL:200 - 500 ng/spot and CHL-50-250 ng/spot

---

TEL:0.09,

CHL: 0.38

---

TEL,

CHL

Bulk and pharmaceutical dosage Form

Precoated silica gel 60F254

---

Acetonitrile: Toluene: Glacial acetic acid (7.5: 2.5: 0.05 v/v/v)

---

242 nm

---

TEL:0.26±0.02,

CHL: 0.67±0.02

---

AMI, ATN, CHL

Pharmaceutical dosage Form

Silica

gel 60F254

---

Chloroform–

Methanol–Ammonia 27%, w/w (9 + 2 + 0.3 v/v/v)

---

274 nm

AMI: 0.1–0.5,

ATN:

0.8–5.0,

CHL: 0.3–1.5 μg/b

---

NP: Normal phase; RP: Reverse phase

Table 5: Reported analytical UPLC method for determination of CHL

Sr. No	Drug	Stationary phase	Mobile phase	Flow Rate (mL/min)	Detection wavelength	Ref.
1.	CHL	KR100-5CHI-TBB column (150 mm × 4.6 mm,5μm)	n-Hexane: 2-Proponol: Acetic acid: Triethylamine (92:8:0.3:0.01 v/v)	1.2	260 nm	91
2.	LOS, CHL	HSS C18 100 mm x 2.1x 1.8 μm column	560 mL of solution A (1.36 g of potassium dihydrogen phosphate buffer, pH 3.0) and 440 mL of solution B (Acetonitrile: Methanol 9:1)	0.4	230 nm	92
3.	CDC, CHL	Dionex C18 column 50 × 2.1 mm, 2.2 µm particle size	5 mM, 6.2 ± 0.5 pH ammonium acetate buffer – acetonitrile	0.5	215 nm	93
4.	AZL, CHL	UPLC BEH C8 50 × 2.1mm i.d.	Phosphate buffer solution:- Acetonitrile (50 : 50)	0.31	254 nm	94

CONCLUSION:

The present review article provides comprehensive data of various analytical and bioanalytical methods developed for CHL alone and in combinations. For analysis purpose, different analytical methods have been reported that includes HPLC, HPTLC, UPLC, UV spectroscopy, etc. The method along with their details concerning the mobile phase, stationary phase, retention time, etc., have been summarized in tabular form that will be more helpful for the researchers for further analytical method development for estimation of CHL in dosage form and pure form. In the future, enlisted data can be used for the development of analytical methods bio-analysis of CHL in pharmaceutical and biological formulations. Finally, it presents an opportunity for greater information on what has already been done and what new methods and changes can be developed to get a better estimation of CHL.

ACKNOWLEDGMENTS:

Authors are thankful to TSPM’s, Trimurti Institute of Pharmacy, Paldhi (Bk) – 425 103, Jalgaon, Maharashtra, India for providing necessary library facilities.

CONFLICT OF INTEREST:

The authors declare that no conflict of interest.

ABBREVIATIONS:

1. µg/mL - Micro Gram per Milliliter

2. HPLC - High-Performance Liquid Chromatography

3. HPTLC - High-Performance Thin Layer Chromatography

4. LC-MS/MS - Liquid Chromatography-Mass Spectroscopy-Mass Spectroscopy

5. UPLC – Ultra Performance Liquid Chromatography

6. nm - Nano Meter

7. NP – Normal Phase

8. RP - Reverse Phase

9. UV/VIS - Ultra Violet/Visible Spectroscopy

10. PDA - Photo Diode Array

11. GAA – Glacial Acetic Acid

12. CHL - Chlorthalidone

13. ATN - Atenolol

14. CE - Celiprolol HCl

15. AZL - Azilsartan Medoxomil

16. CAN - Candesartan

17. CIL - Cilnidipine

18. LOS - Losartan Potassium

19. OLM - Olmesartan Medoxomil

20. NVH - Nebivolol Hydrochloride

21. MET - Metoprolol Tartrate

22. TEL - Telmisartan

23. AMI - Amiloride Hydrochloride

24. AML - Amlodipine

25. CDC - Candesartan Cilexetil

26. IBS - Irbesartan

27. HTZ - Hydrochlorothiazide

28. BEN - Benidipine

29. EPM - Eprosartan Mesylate

30. AMB - Amlodipine Besylate

31. VAL - Valsartan

32. ENM - Enalapril Maleate

33. MPS - Metoprolol Succinate

34. BEN - Benidipine Hydrochloride

35. CLH - Clonidine Hydrochloride

36. WHO - World Health Organization

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Received on 09.07.2021 Modified on 22.11.2021

Res. J. Pharma. Dosage Forms and Tech.2022; 14(1):63-71.

DOI: 10.52711/0975-4377.2022.00011